Dual-acting antihypertensive agents

ABSTRACT

The invention relates to compounds having the formula: 
                         
wherein: Q, W, Y, Z, r, and Ar are as defined in the specification, and pharmaceutically acceptable salts thereof. These compounds have AT 1  receptor antagonist activity and neprilysin inhibition activity. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No.12/431,056, filed Apr. 28, 2009, now allowed, which claims the benefitof U.S. Provisional Application No. 61/048,806, filed on Apr. 29, 2008;the entire disclosures of which are incorporated herein by reference intheir entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds having angiotensin IItype 1 (AT₁) receptor antagonist activity and neprilysin-inhibitionactivity. The invention also relates to pharmaceutical compositionscomprising such compounds, processes and intermediates for preparingsuch compounds and methods of using such compounds to treat diseasessuch as hypertension.

2. State of the Art

The aim of antihypertensive therapy is to lower blood pressure andprevent hypertension-related complications such as myocardialinfarction, stroke, and renal disease. For patients with uncomplicatedhypertension (e.g., no risk factors, target organ damage, orcardiovascular disease), it is hoped that reducing blood pressure willprevent development of cardiovascular and renal comorbidities,conditions that exist at the same time as the primary condition in thesame patient. For those patients with existing risk factors orcomorbidities, the therapeutic target is the slowing of comorbid diseaseprogression and reduced mortality.

Physicians generally prescribe pharmacological therapies for patientswhose blood pressure cannot be adequately controlled by dietary and/orlifestyle modifications. Commonly used therapeutic classes act topromote diuresis, adrenergic inhibition, or vasodilation. A combinationof drugs is often prescribed, depending upon what comorbidities arepresent.

There are five common drug classes used to treat hypertension:diuretics, which include thiazide and thiazide-like diuretics such ashydrochlorothiazide, loop diuretics such as furosemide, andpotassium-sparing diuretics such as triamterene; β₁ adrenergic receptorblockers such as metoprolol succinate and carvedilol; calcium channelblockers such as amlodipine; angiotensin-converting enzyme (ACE)inhibitors such as captopril, benazepril, enalapril, enalaprilat,lisinopril, quinapril, and ramipril; and AT₁ receptor antagonists, alsoknown as angiotensin II type 1 receptor blockers (ARBs), such ascandesartan cilexetil, eprosartan, irbesartan, losartan, olmesartanmedoxomil, telmisartan, and valsartan. Combinations of these drugs arealso administered, for example, a calcium channel blocker (amlodipine)and an ACE inhibitor (benazepril), or a diuretic (hydrochlorothiazide)and an ACE inhibitor (enalapril). All of these drugs, when usedappropriately, are effective in the treatment of hypertension.Nevertheless, both efficacy and tolerability should be further improvedin new drugs targeting hypertension. Despite the availability of manytreatment options, the recent National Health And Nutrition ExaminationSurvey (NHANES) demonstrated that only about 50% of all treated patientswith hypertension achieve adequate blood pressure control. Furthermore,poor patient compliance due to tolerability issues with availabletreatments further reduces treatment success.

In addition, each of the major classes of antihypertensive agents havesome drawbacks. Diuretics can adversely affect lipid and glucosemetabolism, and are associated with other side effects, includingorthostatic hypotension, hypokalemia, and hyperuricemia. Beta blockerscan cause fatigue, insomnia, and impotence; and some beta blockers canalso cause reduced cardiac output and bradycardia, which may beundesirable in some patient groups. Calcium channel blockers are widelyused but it is debatable as to how effectively these drugs reduce fataland nonfatal cardiac events relative to other drug classes. ACEinhibitors can cause coughing, and rarer side effects include rash,angioedema, hyperkalemia, and functional renal failure. AT₁ receptorantagonists are equally effective as ACE inhibitors but without the highprevalence of cough.

Neprilysin (neutral endopeptidase, EC 3.4.24.11) (NEP), is anendothelial membrane bound Zn²⁺ metallopeptidase found in many tissues,including the brain, kidney, lungs, gastrointestinal tract, heart, andperipheral vasculature. NEP is responsible for the degradation andinactivation of a number of vasoactive peptides, such as circulatingbradykinin and angiotensin peptides, as well as the natriureticpeptides, the latter of which have several effects includingvasodilation and diuresis. Thus, NEP plays an important role in bloodpressure homeostasis. NEP inhibitors have been studied as potentialtherapeutics, and include thiorphan, candoxatril, and candoxatrilat. Inaddition, compounds have also been designed that inhibit both NEP andACE, and include omapatrilat, gempatrilat, and sampatrilat. Referred toas vasopeptidase inhibitors, this class of compounds are described inRobl et al. (1999) Exp. Opin. Ther. Patents 9(12): 1665-1677.

There may be an opportunity to increase anti-hypertensive efficacy whencombining AT₁ receptor antagonism and NEP inhibition, as evidenced byAT₁ receptor antagonist/NEP inhibitor combinations described in WO9213564 to Darrow et al. (Schering Corporation); US20030144215 toKsander et al.; Pu et al., Abstract presented at the CanadianCardiovascular Congress (October 2004); Gardiner et al. (2006) JPET319:340-348; and WO 2007/045663 (Novartis AG) to Glasspool et al.

Recently, WO 2007/056546 (Novartis AG) to Feng et al. has describedcomplexes of an AT₁ receptor antagonist and a NEP inhibitor, where anAT₁ receptor antagonist compound is non-covalently bond to a NEPinhibitor compound, or where the antagonist compound is linked to theinhibitor compound by a cation.

In spite of the advances in the art, there remains a need for a highlyefficacious monotherapy with multiple mechanisms of action leading tolevels of blood pressure control that can currently only be achievedwith combination therapy. Compounds having either AT₁ receptorantagonist or NEP inhibitory activity are known, but no single compoundhaving both AT₁ receptor antagonist and NEP inhibitory activity has beenreported. Thus, although various hypertensive agents are known, andadministered in various combinations, it would be highly desirable toprovide single compounds having both AT₁ receptor antagonist activityand NEP inhibition activity in the same molecule. Compounds possessingboth of these activities are expected to be particularly useful astherapeutic agents since they would exhibit antihypertensive activitythrough two independent modes of action while having single moleculepharmacokinetics.

In addition, such dual-acting compounds are also expected to haveutility to treat a variety of other diseases that can be treated byantagonizing the AT₁ receptor and/or inhibiting the NEP enzyme.

SUMMARY OF THE INVENTION

The present invention provides novel compounds that have been found topossess AT₁ receptor antagonist activity and neprilysin (NEP) enzymeinhibition activity. Accordingly, compounds of the invention areexpected to be useful and advantageous as therapeutic agents fortreating conditions such as hypertension and heart failure.

One aspect of the invention relates to a compound of formula I:

wherein:

Y is:

Q is —C(R³)—, and Z is a bond and W is —N—, or Z is —C(O)— and W is—CH—;or

Y is:

Q is —C(R³)—, Z is —C(O)—, and W is —N—;

R¹ is selected from —C₁₋₆alkylene-OH, —COOR^(1a), —CHO,—C₁₋₃alkylene-NHCH(COOH)(C₁₋₆alkyl), —C(O)NHCH(COOH)(C₁₋₆alkyl), and—C(O)NHCH₂R^(1b); where R^(1a) is H or —C₁₋₆alkyl; and R^(1b) is—C₀₋₃alkylenearyl or —C₀₋₃alkyleneheteroaryl;

R² is selected from H, —CH₂OH, halo, —NO₂, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₃₋₆cycloalkyl, —CN, —C(O)R^(2a), and —C₀₋₃alkylenearyl; where R^(2a)is H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —C₀₋₃alkylene-phenyl, —OR^(2b), or—NR^(2c)R^(2d); R^(2b) is H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, phenyl, orbenzyl; and R^(2c) and R^(2d) are independently H, —C₁₋₄alkyl, or—C₀₋₁alkylene-phenyl;

R³ is selected from —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₃₋₁₀alkynyl,—C₀₋₃alkylene-C₃₋₇cycloalkyl, —C₂₋₃alkenylene-C₃₋₇cycloalkyl,—C₂₋₃alkynylene-C₃₋₇cycloalkyl,—C₀₋₅alkylene-NR^(3a)—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-S—C₁₋₅alkylene-R^(3b), and —C₀₋₃alkylencaryl; R^(3a) is H,—C₁₋₆alkyl, —C₃₋₇cycloalkyl, or —C₀₋₃alkylenearyl; and R^(3b) is H,—C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, or aryl;

r is 0, 1 or 2;

Ar—X—CR⁵R⁶R⁷ is selected from:

X is selected from —SO₂NHC(O)—, —SO₂NHC(O)—C₁₋₁₂alkylene-NHC(O)—,—SO₂NHC(O)—C₁₋₁₂alkylene-C(O)NH—, —C(O)NH—SO₂—C₁₋₁₂alkylene-NHC(O)—,—C(O)NH—SO₂—C₁₋₁₂alkylene-C(O)NH—, —SO₂NHC(O)NH—C₂₋₁₂alkylene-NHC(O)—,—SO₂NHC(O)NH—C₁₋₁₂alkylene-C(O)NH—,—NH—SO₂—NHC(O)—C₁₋₁₂alkylene-NHC(O)—, and—NH—SO₂—NHC(O)—C₁₋₁₂alkylene-C(O)NH—;

R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5a))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f),—C₀₋₂alkylene-CHR^(5g)—COOH, —C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH,and —C₀₋₃alkylene-S—SR^(5j); R^(5a) is H or —C(O)R^(5aa); R^(5aa) is—C₁₋₆alkyl, —C₀₋₆alkylene-C₃₋₇cycloalkyl, —C₀₋₆alkylenearyl,—C₀₋₆alkyleneheteroaryl, —C₀₋₆alkylenemorpholine,—C₀₋₆alkylene-piperazine-CH₃, —CH[N(R^(5ab))₂]-aa where aa is an aminoacid side chain, -2-pyrrolidine, —C₀₋₆alkylene-OR^(5ab),—O—C₀₋₆alkylenearyl, —C₁₋₂alkylene-OC(O)—C₁₋₆alkyl,—C₁₋₂alkylene-OC(O)—C₀₋₆alkylenearyl, or—O—C₁₋₂alkylene-OC(O)O—C₁₋₆alkyl; R^(5ab) is independently H or—C₁₋₆alkyl; R^(5b) is H, —OH, —OC(O)R^(5ba), —CH₂COOH, —O-benzyl,-pyridyl, or —OC(S)NR^(5bb)R^(5bc); R^(5ba) is H, —C₁₋₆alkyl, aryl,—OCH₂-aryl, —CH₂O-aryl, or —NR^(5bb)R^(5bc); R^(5bb) and R^(5bc) areindependently H or —C₁₋₄alkyl; R^(5c) is H, —C₁₋₆alkyl, or—C(O)—R^(5ca); R^(5ca) is H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, aryl, orheteroaryl; R^(5d) is H, —C₁₋₄alkyl, —C₀₋₃alkylenearyl,—NR^(5da)R^(5db), —CH₂SH, or —O—C₁₋₆alkyl; R^(5da) and R^(5db) areindependently H or —C₁₋₄alkyl; R^(5e) is H, —C₁₋₆alkyl,—C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl,—CH(CH₃)—O—C(O)R^(5ea),

R^(5ea) is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(5eb)R^(5ec), or—CH(NH₂)CH₂COOCH₃; R^(5eb) and R^(5ec) are independently H, —C₁₋₄alkyl,or —C₁₋₃alkylenearyl, or are taken together as —(CH₂)₃₋₆—; R^(5f) is H,—C₁₋₄alkyl, —C₀₋₃alkylenearyl, —C₁₋₃alkylene-NR^(5fa)R^(5fb), or—C₁₋₃alkylene(aryl)-C₀₋₃alkylene-NR^(5fa)R^(5fb); R^(5fa) and R^(5fb)are independently H or —C₁₋₄alkyl; R^(5g) is H, —C₁₋₆alkyl,—C₁₋₃alkylenearyl, or —CH₂—O—(CH₂)₂—OCH₃; R^(5h) is H or —C₁₋₄alkyl;R^(5i) is H, —C₁₋₄alkyl, or —C₀₋₃alkylenearyl; and R^(5j) is —C₁₋₆alkyl,aryl, or —CH₂CH(NH₂)COOH;

R⁶ is selected from —C₁₋₆alkyl, —CH₂—O—(CH₂)₂—OCH₃,—C₁₋₆alkylene-O—C₁₋₆alkyl, —C₀₋₃alkylenearyl, —C₀₋₃alkyleneheteroaryl,and —C₀₋₃alkylene-C₃₋₇cycloalkyl; and

R⁷ is H or is taken together with R⁶ to form —C₃₋₈cycloalkyl;

wherein: each —CH₂— group in —(CH₂)_(r)— is optionally substituted with1 or 2 substituents independently selected from —C₁₋₄alkyl and fluoro;

one —CH₂— in the —C₁₋₁₂alkylene- portion of X is optionally replacedwith —C₄₋₈cycloalkylene- or phenylene; one or more —CH₂— moieties areoptionally replaced with a —NR⁴—C(O)— or —C(O)—NR⁴— moiety, where R⁴ isH, —OH, or —C₁₋₄alkyl; and one or more —CH₂— moieties are optionallysubstituted with —COOH or an amino acid side chain;

each alkyl and each aryl in R¹⁻⁶ is optionally substituted with 1 to 7fluoro atoms;

each ring in Ar—X—CR⁵R⁶R⁷ and each aryl and heteroaryl in R¹, R², R³,and R⁵⁻⁶ is optionally substituted with 1 to 3 substituentsindependently selected from —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl,—CN, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl,—S(O)₂—C₁₋₄alkyl, phenyl, —NO₂, —NH₂, —NH—C₁₋₆alkyl, and —N(C₁₋₆alkyl)₂,wherein each alkyl, alkenyl and alkynyl is optionally substituted with 1to 5 fluoro atoms;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a compound of theinvention. Such compositions may optionally contain other therapeuticactive agents such as diuretics, β₁ adrenergic receptor blockers,calcium channel blockers, angiotensin-converting enzyme inhibitors, AT₁receptor antagonists, neprilysin inhibitors, non-steroidalanti-inflammatory agents, prostaglandins, anti-lipid agents,anti-diabetic agents, anti-thrombotic agents, renin inhibitors,endothelin receptor antagonists, endothelin converting enzymeinhibitors, aldosterone antagonists, angiotensin-convertingenzyme/neprilysin inhibitors, vasopressin receptor antagonists, andcombinations thereof. Accordingly, in yet another aspect of theinvention, a pharmaceutical composition comprises a compound of theinvention, a second therapeutic agent, and a pharmaceutically acceptablecarrier. Another aspect of the invention relates to a combination ofactive agents, comprising a compound of the invention and a secondtherapeutic agent. The compound of the invention can be formulatedtogether or separately from the additional agent(s). When formulatedseparately, a pharmaceutically acceptable carrier may be included withthe additional agent(s). Thus, yet another aspect of the inventionrelates to a combination of pharmaceutical compositions, the combinationcomprising: a first pharmaceutical composition comprising a compound ofthe invention and a first pharmaceutically acceptable carrier; and asecond pharmaceutical composition comprising a second therapeutic agentand a second pharmaceutically acceptable carrier. The invention alsorelates to a kit containing such pharmaceutical compositions, forexample where the first and second pharmaceutical compositions areseparate pharmaceutical compositions.

Compounds of the invention possess both AT₁ receptor antagonist activityand NEP enzyme inhibition activity, and are therefore expected to beuseful as therapeutic agents for treating patients suffering from adisease or disorder that is treated by antagonizing the AT₁ receptorand/or inhibiting the NEP enzyme. Thus, one aspect of the inventionrelates to a method of treating patients suffering from a disease ordisorder that is treated by antagonizing the AT₁ receptor and/orinhibiting the NEP enzyme, comprising administering to a patient atherapeutically effective amount of a compound of the invention. Anotheraspect of the invention relates to a method of treating hypertension orheart failure, comprising administering to a patient a therapeuticallyeffective amount of a compound of the invention. Still another aspect ofthe invention relates to a method for antagonizing an AT₁ receptor in amammal comprising administering to the mammal, an AT₁receptor-antagonizing amount of a compound of the invention. Yet anotheraspect of the invention relates to a method for inhibiting a NEP enzymein a mammal comprising administering to the mammal, a NEPenzyme-inhibiting amount of a compound of the invention.

Compounds of the invention that are of particular interest include thosethat exhibit an inhibitory constant (pK_(i)) for binding to an AT₁receptor greater than or equal to about 5.0; in particular those havinga pK_(i) greater than or equal to about 6.0; in one embodiment thosehaving a pK_(i) greater than or equal to about 7.0; more particularlythose having a pK_(i) greater than or equal to about 8.0; and in yetanother embodiment, those having a pK_(i) within the range of about8.0-10.0. Compounds of particular interest also include those having aNEP enzyme inhibitory concentration (pIC₅₀) greater than or equal toabout 5.0; in one embodiment those having a pIC₅₀ greater than or equalto about 6.0; in particular those having a pIC₅₀ greater than or equalto about 7.0; and most particularly those having a pIC₅₀ within therange of about 7.0-10.0. Compounds of further interest include thosehaving a pK_(i) for binding to an AT₁ receptor greater than or equal toabout 7.5 and having a NEP enzyme pIC₅₀ greater than or equal to about7.0.

Since compounds of the invention possess AT₁ receptor antagonistactivity and NEP inhibition activity, such compounds are also useful asresearch tools. Accordingly, one aspect of the invention relates to amethod of using a compound of the invention as a research tool, themethod comprising conducting a biological assay using a compound of theinvention. Compounds of the invention can also be used to evaluate newchemical compounds. Thus another aspect of the invention relates to amethod of evaluating a test compound in a biological assay, comprising:(a) conducting a biological assay with a test compound to provide afirst assay value; (b) conducting the biological assay with a compoundof the invention to provide a second assay value; wherein step (a) isconducted either before, after or concurrently with step (b); and (c)comparing the first assay value from step (a) with the second assayvalue from step (b). Exemplary biological assays include an AT₁ receptorbinding assay and a NEP enzyme inhibition assay. Still another aspect ofthe invention relates to a method of studying a biological system orsample comprising an AT₁ receptor, a NEP enzyme, or both, the methodcomprising: (a) contacting the biological system or sample with acompound of the invention; and (b) determining the effects caused by thecompound on the biological system or sample.

The invention is also directed to processes and intermediates useful forpreparing compounds of the invention. Accordingly, another aspect of theinvention relates to a process of preparing compounds of the inventioncomprising the step of coupling a compound of formula 1 with a compoundof formula 2:

or coupling a compound of formula 1′ with a compound of formula 2′:

where: A is —NH₂ and B is —COOH or A is —COOH and B is —NH₂; the sum ofa and b is in the range of 1 to 12; and R⁵* represents R⁵ or a protectedform of R⁵; and optionally deprotecting the product when R⁵* is aprotected form of R⁵. Another aspect of the invention relates to aprocess of preparing a pharmaceutically acceptable salt of a compound offormula I, comprising contacting a compound of formula I in free acid orbase form with a pharmaceutically acceptable base or acid. In otheraspects, the invention relates to products prepared by any of theprocesses described herein, as well as novel intermediates used in suchprocess. In one aspect of the invention, these novel intermediates haveformula II.

Yet another aspect of the invention relates to the use of a compound ofthe invention for the manufacture of a medicament, especially for themanufacture of a medicament useful for treating hypertension or acutedecompensated heart failure. Another aspect of the invention relates touse of a compound of the invention for antagonizing an AT₁ receptor orfor inhibiting a NEP enzyme in a mammal. Still another aspect of theinvention relates to the use of a compound of the invention as aresearch tool. Other aspects and embodiments of the invention aredisclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to compounds of formula I:

and pharmaceutically acceptable salts thereof.

As used herein, the term “compound of the invention” includes allcompounds of encompassed by formula I such as the species embodied informulas Ia, Ib, Ic, and Id, described below. In addition, the compoundsof the invention may also contain several basic or acidic groups (e.g.,amino or carboxyl groups) and therefore, such compounds can exist as afree base, free acid, or in various salt forms. All such salt forms areincluded within the scope of the invention. Finally, the compounds ofthe invention may also exist as prodrugs. Accordingly, those skilled inthe art will recognize that reference to a compound herein, for example,reference to a “compound of the invention” or a “compound of formula I”includes reference to a compound of formula I as well as topharmaceutically acceptable salts and prodrugs of that compound unlessotherwise indicated. Further, the term “or a pharmaceutically acceptablesalt and/or prodrug thereof” is intended to include all permutations ofsalts and prodrugs, such as a pharmaceutically acceptable salt of aprodrug. Furthermore, solvates of compounds of formula I or saltsthereof are included within the scope of the invention.

The compounds of formula I may contain one or more chiral centers andtherefore, these compounds may be prepared and used in variousstereoisomeric forms. Accordingly, the invention relates to racemicmixtures, pure stereoisomers (enantiomers or diastereomers),stereoisomer-enriched mixtures, and the like unless otherwise indicated.When a chemical structure is depicted herein without anystereochemistry, it is understood that all possible stereoisomers areencompassed by such structure. Thus, for example, the term “compound offormula I” is intended to include all possible stereoisomers of thecompound. Similarly, when a particular stereoisomer is shown or namedherein, it will be understood by those skilled in the art that minoramounts of other stereoisomers may be present in the compositions of theinvention unless otherwise indicated, provided that the utility of thecomposition as a whole is not eliminated by the presence of such otherisomers. Individual enantiomers may be obtained by numerous methods thatare well known in the art, including chiral chromatography using asuitable chiral stationary phase or support, or by chemically convertingthem into diastereomers, separating the diastereomers by conventionalmeans such as chromatography or recrystallization, then regenerating theoriginal enantiomers. Additionally, where applicable, all cis-trans orE/Z isomers (geometric isomers), tautomeric forms and topoisomeric formsof the compounds of the invention are included within the scope of theinvention unless otherwise specified.

One possible chiral center could be present in the —CR⁵R⁶R⁷ portion ofthe compound, when R⁶ is a group such as —C₁₋₆alkyl, for example—CH₂CH(CH₃)₂, and R⁷ is H. This chiral center is present at the carbonatom indicated by the symbol * in the following formula:

In one embodiment of the invention, the carbon atom identified by thesymbol * has the (R) configuration. In this embodiment, compounds offormula I have the (R) configuration at the carbon atom identified bythe symbol * or are enriched in a stereoisomeric form having the (R)configuration at this carbon atom (or atoms). In another embodiment, thecarbon atom identified by the symbol * has the (S) configuration. Inthis embodiment, compounds of formula I have the (S) configuration atthe carbon atom identified by the symbol * or are enriched in astereoisomeric form having the (S) configuration at this carbon atom. Insome cases, in order to optimize the therapeutic activity of thecompounds of the invention, for example, as hypertensive agents, it maybe desirable that the carbon atom identified by the symbol * have aparticular (R) or (S) configuration. It is understood that a compoundmay have two chiral centers, i.e., at the * carbon atom and at a secondcarbon atom. In such cases, four possible diastereomers can exist. Insome cases, in order to optimize the therapeutic activity of thecompounds of the invention, e.g., as hypertensive agents, it may bedesirable that the carbon atom identified by the symbol * have aparticular (R) or (S) configuration.

The compounds of the invention, as well as those compounds used in theirsynthesis, may also include isotopically-labeled compounds, i.e., whereone or more atoms have been enriched with atoms having an atomic massdifferent from the atomic mass predominately found in nature. Examplesof isotopes that may be incorporated into the compounds of formula I,for example, include, but are not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N,¹⁸O, ¹⁷O, ³⁵S, ³⁶Cl, and ¹⁸F.

The compounds of formula I have been found to possess AT₁ receptorantagonizing activity and NEP enzyme inhibition activity. Among otherproperties, such compounds are expected to be useful as therapeuticagents for treating diseases such as hypertension. By combining dualactivity into a single compound, double therapy can be achieved; bothAT₁ receptor antagonist activity and NEP enzyme inhibition activity canbe obtained using a single active component. Since pharmaceuticalcompositions containing one active component are typically easier toformulate than compositions containing two active components, suchsingle-component compositions provide a significant advantage overcompositions containing two active components. In addition, certaincompounds of the invention have also been found to be selective forinhibition of the AT₁ receptor over the angiotensin II type 2 (AT₂)receptor, a property that may have therapeutic advantages.

The nomenclature used herein to name the compounds of the invention isillustrated in the Examples herein. This nomenclature has been derivedusing the commercially-available AutoNom software (MDL, San Leandro,Calif.).

Representative Embodiments

The following substituents and values are intended to providerepresentative examples of various aspects and embodiments of theinvention. These representative values are intended to further defineand illustrate such aspects and embodiments and are not intended toexclude other embodiments or to limit the scope of the invention. Inthis regard, the representation that a particular value or substituentis preferred is not intended in any way to exclude other values orsubstituents from the invention unless specifically indicated.

In one aspect, the invention relates to compounds of formula (I):

In one embodiment of the invention, Y is:

Q is —C(R³)—, and Z is a bond and W is —N—, or Z is —C(O)— and W is—CH—. In this embodiment, formula I can be represented as:

In one particular embodiment, Z is a bond and W is —N—.

In another embodiment of the invention, Y is:

Q is —C(R³)—, Z is —C(O)—, and W is —N—. In this embodiment, formula Ican be represented as:

R¹ is selected from —C₁₋₆alkylene-OH, —COOR^(1a), —CHO,—C₁₋₃alkylene-NHCH(COOH)(C₁₋₆alkyl), —C(O)NHCH(COOH)(C₁₋₆alkyl), and—C(O)NHCH₂R^(1b). The R^(1a) group is H or —C₁₋₆alkyl, and the R^(1b)group is —C₀₋₃alkylenearyl or —C₀₋₃alkyleneheteroaryl.

In one embodiment, R¹ is —C₁₋₆alkylene-OH, for example, R¹ is —CH₂OH. Inanother embodiment, R¹ is —COOR^(1a), and R^(1a) is H. In one particularembodiment, R¹ is —CHO.

In one embodiment, R¹ is —C₁₋₃alkylene-NHCH(COOH)(C₁₋₆alkyl), forexample, —CH₂NHCH(COOH)(C₂₋₅alkyl) such as —CH₂NHCH(COOH)[CH₂CH(CH₃)₂].

In another embodiment, R¹ is —C(O)NHCH(COOH)(C₁₋₆alkyl), for example,—C(O)NHCH(COOH)(C₂₋₅alkyl) such as —C(O)NHCH(COOH)[CH(CH₃)₂].

In one particular embodiment, R¹ is —C(O)NHCH₂R^(1b), and R^(1b) is—C₀₋₃alkylenearyl for example, —C₀₋₃alkylenephenyl. In one suchembodiment, R¹ is —C(O)NHCH₂-phenyl, —C(O)NH(CH₂)₂-phenyl,—C(O)NH(CH₂)₃-phenyl, or —C(O)NH(CH₂)₄-phenyl.

In yet another embodiment, R¹ is —C(O)NHCH₂R^(1b), and R^(1b) is—C₀₋₃alkyleneheteroaryl, for example a —C₀₋₁alkyleneheteroaryl groupsuch as -2-thienyl and —CH₂-2-thienyl. In one such embodiment, R¹ is—C(O)NHCH₂-2-thienyl or —C(O)NH(CH₂)₂-2-thienyl.

Each alkyl and each aryl in R¹ is optionally substituted with 1 to 7fluoro atoms. In addition, the term “alkyl” is intended to includedivalent alkylene groups such as those present in —C₁₋₆alkylene-OH, forexample. Further, each aryl and heteroaryl in R¹, for example in—C₀₋₃alkylenearyl, is optionally substituted with 1 to 3 substituentsindependently selected from —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl,—CN, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl,—S(O)₂—C₁₋₄alkyl, phenyl, —NO₂, —NH₂, —NH—C₁₋₆alkyl, and —N(C₁₋₆alkyl)₂.Further, each of the aforementioned alkyl, alkenyl and alkynyl groups isoptionally substituted with 1 to 5 fluoro atoms. It is understood thatwhen referring to “each alkyl,” “each aryl” and “each heteroaryl” groupin R¹, the terms also include any such groups that might be present inthe R^(1a) and R^(1b) moieties.

R² is selected from H, —CH₂OH, halo, —NO₂, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₃₋₆cycloalkyl, —CN, —C(O)R^(2a), and —C₀₋₃alkylenearyl. The R^(2a)moiety is H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —C₀₋₃alkylene-phenyl, —OR^(2b)or —NR^(2c)R^(2d); where R^(2b) is H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl,phenyl, or benzyl; and R^(2c) and R^(2d) are independently H,—C₁₋₄alkyl, or —C₀₋₁alkylene-phenyl. In one particular embodiment, R² isH or halo, particularly chloro.

Each alkyl and each aryl in R² is optionally substituted with 1 to 7fluoro atoms. In addition, the aryl in R², for example in—C₀₋₃alkylenearyl or —C₀₋₃alkylene-phenyl, may be substituted with 1 to3 —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo, —O(C₁₋₆alkyl),—S(C₁₋₆alkyl), —S(O)(C₁₋₆alkyl), —S(O)₂(C₁₋₄alkyl), phenyl, —NO₂, —NH₂,—NH(C₁₋₆alkyl), or —N(C₁₋₆alkyl)₂ groups. Further, each of theaforementioned alkyl, alkenyl and alkynyl groups may be substituted with1 to 5 fluoro atoms. It is understood that when referring to the “alkyl”and “aryl” groups in R², the term includes any such groups that might bepresent in the R^(2a), R^(2b), R^(2c) and R^(2d) moieties.

R³ is selected from —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₃₋₁₀alkynyl,—C₀₋₃alkylene-C₃₋₇cycloalkyl, —C₂₋₃alkenylene-C₃₋₇cycloalkyl,—C₂₋₃alkynylene-C₃₋₇cycloalkyl,—C₀₋₅alkylene-NR^(3a)—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-S—C₁₋₅alkylene-R^(3b), and —C₀₋₃alkylenearyl. The R^(1a)moiety is H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, or —C₀₋₃alkylenearyl (e.g.,—C₀₋₁alkylenearyl such as phenyl and benzyl). R^(3b) is H, —C₁₋₆alkyl,—C₃₋₇cycloalkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, or aryl (such as phenyl).

In addition, each alkyl and each aryl in R³ is optionally substitutedwith 1 to 7 fluoro atoms, where the term “alkyl” is intended to includedivalent alkylene groups such as those present in—C₀₋₃alkylene-C₃₋₇cycloalkyl and —C₀₋₃alkylenearyl, for example. Eacharyl in R³, for example in —C₀₋₃alkylenearyl or aryl, may be substitutedwith 1 to 3 —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo,—O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, phenyl,—NO₂, —NH₂, —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)₂ groups. Further, each ofthe aforementioned alkyl, alkenyl and alkynyl groups may be substitutedwith 1 to 5 fluoro atoms. It is understood that when referring to the“alkyl” and “aryl” groups in R³, the terms also include any such groupsthat might be present in the R^(3a) and R^(3b) moieties.

In one embodiment, R³ is —C₁₋₁₀alkyl such as —CH₃ or optionallysubstituted with 1 to 7 fluoro atoms such as —CF₃. In anotherembodiment, R³ is —C₂₋₇alkyl such as —CH₂CH₃; and in yet anotherembodiment, R³ is —C₂₋₅alkyl, for example, —(CH₂)₂CH₃, —(CH₂)₃CH₃,—CH₂—CH(CH₃)₂, —CH₂—CH(CH₃)CH₂CH₃, —(CH₂)₂—CH(CH₃)₂, —CH(CH₂CH₃)₂, or—(CH₂)₄CH₃. In one particular embodiment, R³ is —(CH₂)₃CH₃.

In another embodiment, R³ is —C₂₋₁₀alkenyl such as —CH₂CH═CHCH₃. In yetanother embodiment, R³ is —C₃₋₁₀alkynyl such as —CH₂C≡CCH₃.

In another embodiment, R³ is —C₀₋₃alkylene-C₃₋₇cycloalkyl such as-cyclopropyl, —CH₂-cyclopropyl, cyclopentyl, —CH₂-cyclopentyl,—(CH₂)₂-cyclopentyl, and —CH₂-cyclohexyl. In a particular embodiment, R³is —C₀₋₁alkylene-C₃₋₅cycloalkyl. In one embodiment, R³ is—C₂₋₃alkenylene-C₃₋₇cycloalkyl such as —CH₂CH═CH-cyclopentyl; and inanother embodiment, R³ is —C₂₋₃alkynylene-C₃₋₇cycloalkyl such as—CH₂C≡C-cyclopentyl.

In yet another embodiment, R³ is—C₀₋₅alkylene-NR^(3a)—C₀₋₅alkylene-R^(3b). In one particular embodiment,R^(3a) is H and R^(3b) is —C₁₋₆alkyl. Examples of such R³ groups include—NHCH₂CH₃, —NHCH(CH₃)₂, —NH(CH₂)₂CH₃, —NH(CH₂)₃CH₃, —NHCH(CH₃)CH₂CH₃,—NH(CH₂)₄CH₃, and —NH(CH₂)₅CH₃.

In one embodiment, R³ is —C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b). In oneparticular embodiment, R^(3b) is H, —C₁₋₆alkyl, or aryl. Examples ofsuch R³ groups include —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —O(CH₂)₂CH₃,—O(CH₂)₃CH₃, —OCH₂CH(CH₃)₂, —O-phenyl, and —O-benzyl.

In another embodiment, R³ is —C₀₋₅alkylene-S—C₁₋₅alkylene-R^(3b), and inone particular embodiment R^(3b) is H, such as when R³ is —CH₂—S—CH₂CH₃.In another embodiment, R³ is —C₀₋₃alkylenearyl, such as phenyl, benzyl,and —(CH₂)₂-phenyl.

The values for r are 0, 1 or 2. In one embodiment, r is 1. Each —CH₂—group in the —(CH₂)_(r)— group may be substituted with 1 or 2substituents independently selected from —C₁₋₄alkyl (e.g., —CH₃), andfluoro. In one particular embodiment, the —(CH₂)_(r)— group isunsubstituted; in another embodiment, one or two —CH₂— groups in—(CH₂)_(r)— are substituted with a —C₁₋₄alkyl group.

Ar—X—CR⁵R⁶R⁷ represents an aryl group selected from:

Each ring in the Ar portion may be substituted with 1 to 3 substituentsindependently selected from —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl,—CN, halo, —O—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, phenyl,—NO₂, —NH₂, —NH—C₁₋₆alkyl and —N(C₁₋₆alkyl)₂. Furthermore, each of theaforementioned alkyl, alkenyl and alkynyl groups are optionallysubstituted with 1 to 5 fluoro atoms.

In one particular embodiment, each ring in the Ar portion may besubstituted with 1 to 2 substituents independently selected from —OH,—C₁₋₄alkyl (e.g., —CH₃), halo (e.g., bromo, fluoro, chloro, anddi-fluoro), —O—C₁₋₄alkyl (e.g., —OCH₃), and phenyl. Exemplarysubstituted Ar—X—CR⁵R⁶R⁷ moieties include:

Of particular interest is where Ar is substituted with 1 or 2 haloatoms.

It is understood that:

represents:

In one particular embodiment, Ar—X—CR⁵R⁶R⁷ is an aryl group selectedfrom:

X is —SO₂NHC(O)—, —SO₂NHC(O)—C₁₋₁₂alkylene-NHC(O)—,—SO₂NHC(O)—C₁₋₁₂alkylene-C(O)NH—, —C(O)NH—SO₂—C₁₋₁₂alkylene-NHC(O)—,—C(O)NH—SO₂—C₁₋₁₂alkylene-C(O)NH—, —SO₂NHC(O)NH—C₂₋₁₂alkylene-NHC(O)—,—SO₂NHC(O)NH—C₁₋₁₂alkylene-C(O)NH—,—NH—SO₂—NHC(O)—C₁₋₁₂alkylene-NHC(O)—, or—NH—SO₂—NHC(O)—C₁₋₁₂alkylene-C(O)NH—.

In one embodiment, X is —SO₂NHC(O)—. In another embodiment, X contains a—C₁₋₁₂alkylene- group; thus X can contain a —C₁alkylene-, —C₂alkylene-,—C₃alkylene-, —C₄alkylene-, —C₅alkylene-, —C₆alkylene-, —C₇alkylene-,—C₈alkylene, —C₉alkylene-, —C₁₀alkylene-, —C₁₁alkylene- or —C₁₂alkylene-group. In another embodiment, X is SO₂NHC(O)— or—SO₂NHC(O)—C₁₋₉alkylene-NHC(O)—; and in another embodiment, X is—SO₂NHC(O)— or —SO₂NHC(O)—C₁₋₅alkylene-NHC(O)—.

In another embodiment, X is —SO₂NHC(O)—C₁₋₁₂alkylene-C(O)NH—, such as—SO₂NHC(O)—C₁₋₅alkylene-C(O)NH—. In yet another embodiment, X is—C(O)NH—SO₂—C₁₋₁₂alkylene-NHC(O)—, such as—C(O)NH—SO₂—C₁₋₆alkylene-NHC(O)—. In one embodiment, X is—C(O)NH—SO₂—C₁₋₁₂alkylene-C(O)NH—, such as—C(O)NH—SO₂—C₁₋₆alkylene-C(O)NH—. In yet another embodiment, X is—SO₂NHC(O)NH—C₂₋₁₂alkylene-NHC(O)—, such as—SO₂NHC(O)NH—C₂₋₅alkylene-NHC(O)—. In one embodiment, X is—SO₂NHC(O)NH—C₁₋₁₂alkylene-C(O)NH—, such as—SO₂NHC(O)NH—C₁₋₅alkylene-C(O)NH—. In yet another embodiment, X is—NH—SO₂—NHC(O)—C₁₋₁₂alkylene-NHC(O)—, such as—NH—SO₂—NHC(O)—C₁₋₆alkylene-NHC(O)—. In another embodiment, X is—NH—SO₂—NHC(O)—C₁₋₁₂alkylene-C(O)NH—, such as—NH—SO₂—NHC(O)—C₁₋₆alkylene-C(O)NH—.

One or more —CH₂— moieties in the —C₁₋₁₂alkylene- portion of X areoptionally replaced with a —NR⁴—C(O)— or —C(O)—NR⁴— moiety. In oneembodiment, none of the —CH₂-moieties are replaced with a —NR⁴—C(O)— or—C(O)—NR⁴— group. In another embodiment, at least one of the —CH₂—moieties is replaced with a —NR⁴—C(O)— or —C(O)—NR⁴— group, and inanother embodiment 1, 2 or 3 of the —CH₂— moieties are replaced. Inanother embodiment, when more than one —CH₂— moiety is replaced with a—NR⁴—C(O)— or —C(O)—NR⁴— moiety, then the replaced moieties arenon-contiguous.

R⁴ is selected from H, —OH, and —C₁₋₄alkyl. In one particularembodiment, R⁴ is H. In another embodiment, R⁴ is —C₁₋₄alkyl, examplesof which include —CH(CH₃)₂, i.e., X can be a group such as—SO₂NHC(O)CH(CH(CH₃)₂)—C₂₋₁₂alkylene-. Each alkyl in R⁴ is optionallysubstituted with 1 to 7 fluoro atoms.

One —CH₂— in the —C₁₋₁₂alkylene- portion of X may be replaced with a—C₄₋₈cycloalkylene- or phenylene group. The point of attachment for the—C₄₋₈cycloalkylene- or phenylene group is at any available carbon.Examples of cycloalkyl-containing X groups include—SO₂NHC(O)-cyclopentylene-NHC(O)—, —SO₂NHC(O)-cyclohexylene-NHC(O)—, and—SO₂—NHC(O)CH₂—CH₂—NHC(O)-cyclohexylene-NHC(O)—. Examples ofphenylene-containing X groups include —SO₂NHC(O)-phenyl-NHC(O)—. Incertain embodiments, the phenylene group is attached at the meta or paraposition.

In addition, one or more of the —CH₂— groups in the —C₁₋₁₂alkylene-portion of X may be substituted with a —COOH moiety or an amino acidside chain (e.g., the side chain —CH(CH₃)₂). In one embodiment, thereare no such substitutions. In another embodiment, one of the —CH₂—groups is substituted with —COOH.

Exemplary X groups include the following:

—SO₂NHC(O)—

—SO₂NHC(O)—C₁alkylene- with no —CH₂— moieties replaced:

-   -   —SO₂NHC(O)CH[CH(CH₃)₂]—NHC(O)—    -   —SO₂NHC(O)CH₂—NHC(O)—

—SO₂NHC(O)—C₁alkylene with one —CH₂— moiety replaced:

-   -   —SO₂NHC(O)-cyclopentylene-NHC(O)—    -   —SO₂NHC(O)-cyclohexylene-NHC(O)—

—SO₂NHC(O)—C₂alkylene with no —CH₂— moieties replaced:

-   -   —SO₂NHC(O)(CH₂)₂—NHC(O)—

—SO₂NHC(O)—C₁alkylene with one —CH₂— moieties replaced:

-   -   —SO₂NHC(O)CH₂—NHC(O)—CH₂—NHC(O)—

—SO₂NHC(O)—C₄alkylene with no —CH₂— moieties replaced:

-   -   —SO₂NHC(O)(CH₂)₄—NHC(O)—

—SO₂NHC(O)—C₄alkylene with one —CH₂— moiety replaced:

-   -   —SO₂NHC(O)(CH₂)₂—NHC(O)—CH₂—NHC(O)—    -   —SO₂NHC(O)—C₄alkylene with two —CH₂— moieties replaced:    -   —SO₂—NHC(O)(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—

—SO₂NHC(O)—C₅alkylene with one —CH₂— moiety replaced:

-   -   —SO₂NHC(O)(CH₂)₂—NHC(O)—CH₂—CH(COOH)—NHC(O)—

—SO₂NHC(O)—C₆alkylene with no —CH₂— moieties replaced:

-   -   —SO₂—NHC(O)(CH₂)₆—NHC(O)—

—SO₂NHC(O)—C₆alkylene with one —CH₂— moiety replaced:

-   -   —SO₂NHC(O)(CH₂)₂—NHC(O)—(CH₂)₂—CH(COOH)—NHC(O)—    -   —SO₂—NHC(O)(CH₂)₄—NHC(O)—CH₂—NHC(O)—

—SO₂NHC(O)—C₈alkylene with one —CH₂— moiety replaced:

-   -   —SO₂NHC(O)(CH₂)₆—NHC(O)—CH₂—NHC(O)—

R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f),—C₀₋₂alkylene-CHR^(5g)—COOH, —C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH,and —C₀₋₃alkylene-S—SR^(5j). Each alkyl and each aryl in R⁵ isoptionally substituted with 1 to 7 fluoro atoms, where the term “alkyl”is intended to include divalent alkylene groups such as those present in—C₀₋₃alkylene-SR^(5a) and —C₀₋₃alkylene-P(O)OR^(5e)R^(5f), for example.Each aryl and heteroaryl in R⁵ may be substituted with 1 to 3 —OH,—C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, phenyl, —NO₂, —NH₂,—NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)₂ groups. Further, each of theaforementioned alkyl, alkenyl and alkynyl groups may be substituted with1 to 5 fluoro atoms. It is understood that when referring to “eachalkyl,” “each aryl” and “each heteroaryl” group in R⁵, the terms alsoinclude any alkyl and aryl groups that might be present in theR^(5a-5j), R^(5aa), R^(5ab), R^(5ba), R^(5bb), R^(5bc), R^(5ca),R^(5da), R^(5db), R^(5ea), R^(5eb), R^(5ec), R^(5fa), and R^(5fb)moieties.

In one embodiment, R⁵ is —C₀₋₃alkylene-SR^(5a). R^(5a) is H or—C(O)R^(5aa). The R^(5aa) group is —C₁₋₆alkyl,—C₀₋₆alkylene-C₃₋₇cycloalkyl, —C₀₋₆alkylenearyl,—C₀₋₆alkyleneheteroaryl, —C₀₋₆alkylenemorpholine,—C₀₋₆alkylenepiperazine-CH₃, —CH[N(R^(5ab))₂]-aa where aa is an aminoacid side chain, -2-pyrrolidine, —C₀₋₆alkylene-OR^(5ab),—O—C₀₋₆alkylenearyl, —C₁₋₂alkylene-OC(O)—C₁₋₆alkyl,—C₁₋₂alkylene-OC(O)—C₀₋₆alkylenearyl, or—O—C₁₋₂alkylene-OC(O)O—C₁₋₆alkyl. The R^(5ab) group is independently Hor —C₁₋₆alkyl. In one specific embodiment, R^(5a) is H, for example, R⁵can be —SH or —CH₂SH. In another embodiment, R^(5a) is —C(O)—R^(5aa),where R^(5aa) is —C₁₋₆alkyl. Exemplary —C₁₋₆alkyl groups include —CH₃,—CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, and —CH₂CH(CH₃)₂. Thus, examples of R⁵include —SC(O)CH₃, —CH₂SC(O)CH₃, —CH₂SC(O)CH₂CH₃, —CH₂SC(O)CH(CH₃)₂ and—CH₂SC(O)C(CH₃)₃, and —CH₂SC(O)CH₂CH(CH₃)₂. In one embodiment, R^(5a) isH or —C(O)—C₁₋₆alkyl.

In one embodiment, R⁵ is —C₀₋₃alkylene-SR^(5a), where R^(5a) is—C(O)—R^(5aa), and R^(5aa) is —C₀₋₆alkylene-C₃₋₇cycloalkyl. ExemplaryC₃₋₇cycloalkyl groups include cyclopentyl and cyclohexyl. Thus, examplesof R⁵ include —CH₂SC(O)-cyclopentyl, —CH₂SC(O)-cyclohexyl, and—CH₂SC(O)—CH₂-cyclopentyl. In another embodiment, R⁵ is—C₀₋₃alkylene-SR^(5a), where R^(5a) is —C(O)—R^(5aa), and R^(5aa) is—C₀₋₆alkylenearyl. In one specific embodiment, the aryl is optionallysubstituted with 1 to 3 substituents such as —O—C₁₋₆alkyl. Exemplaryaryl groups include phenyl and -phenyl-OCH₃. Thus, examples of R⁵include —CH₂SC(O)-phenyl and —CH₂SC(O)-phenyl-OCH₃. In yet anotherembodiment, R⁵ is —C₀₋₃alkylene-SR^(5a), where R^(5a) is —C(O)—R^(5aa),and R^(5aa) is —C₀₋₆alkyleneheteroaryl. Exemplary heteroaryl groupsinclude furanyl, thienyl and pyridinyl. Thus, examples of R⁵ include:—CH₂SC(O)-2-pyridine, —CH₂SC(O)-3-pyridine, and —CH₂SC(O)-4-pyridine.

In another embodiment, R⁵ is —C₀₋₃alkylene-SR^(5a), where R^(5a) is—C(O)—R^(5aa), and R^(5aa) is —C₀₋₆alkylenemorpholine:

more particularly, —C₁₋₃alkylenemorpholine. Thus, examples of R⁵ include—CH₂S—C(O)CH₂-morpholine and —CH₂S—C(O)(CH₂)₂-morpholine. In anotherembodiment, R⁵ is —C₀₋₃alkylene-SR^(5a), where R^(5a) is —C(O)—R^(5aa),and R^(5aa) is —C₀₋₆alkylenepiperazine-CH₃. Thus, examples of R⁵ include—CH₂S—C(O)(CH₂)₂-piperazine-CH₃.

In one embodiment, R⁵ is —C₀₋₃alkylene-SR^(5a), where R^(5a) is—C(O)—R^(5aa), and R^(5aa) is —CH[N(R^(5ab))₂]-aa where aa is an aminoacid side chain. For example, the amino acid side chain could be—CH(CH₃)₂ (valine side chain), —CH₂CH(CH₃)₂ (leucine side chain),—CH(CH₃)CH₂CH₃ (isoleucine side chain), —CH₂COOH (aspartic acid sidechain), —(CH₂)₂COOH (glutamic acid side chain), —CH(OH)(CH₃) (threonineside chain), -benzyl (phenylalanine side chain), -4-hydroxybenzyl(tyrosine side chain), and —(CH₂)₂SCH₃ (methionine side chain). Thus,examples of R⁵ include —CH₂S—C(O)CH(NH₂)—CH(CH₃)₂,—CH₂SC(O)CH(NH₂)—CH₂CH(CH₃)₂, —CH₂SC(O)CH(NH₂)—CH(CH₃)CH₂CH₃,—CH₂SC(O)CH(NH₂)—CH₂COOH, —CH₂SC(O)CH(NH₂)—(CH₂)₂COOH,—CH₂SC(O)CH(NH₂)—CH(OH)(CH₃), —CH₂SC(O)—CH(NH₂)-benzyl,—CH₂SC(O)CH(NH₂)—4-hydroxybenzyl, and —CH₂SC(O)CH(NH₂)—(CH₂)₂SCH₃.

In yet another embodiment, R⁵ is —C₀₋₃alkylene-SR^(5a), where R^(5a) is—C(O)—R^(5aa), and R^(5aa) is −2-pyrrolidine:

Thus, an example of R⁵ is —CH₂S—C(O)-2-pyrrolidine.

In yet another embodiment, R⁵ is —C₀₋₃alkylene-SR^(5a), where R^(5a) is—C(O)—R^(5a), and R^(5aa) is —C₀₋₆alkylene-OR^(5ab). In one embodiment,R^(5ab) is H, such that R^(5a) is —C(O)—C₀₋₆alkylene-OH. In anotherembodiment, R^(5ab) is —C₁₋₆alkyl, such that R^(5a) is—C(O)—C₀₋₆alkylene-O—C₁₋₆alkyl, for example, R⁵ can be—CH₂SC(O)—O—CH₂CH₃.

In yet another embodiment, R⁵ is —C₀₋₃alkylene-SR^(5a), where R^(5a) is—C(O)—R^(5aa), and R^(5aa) is —O—C₀₋₆alkylenearyl. In yet anotherembodiment, R⁵ is —C₀₋₃alkylene-SR^(5a), where R^(5a) is —C(O)—R^(5aa),and R^(5aa) is —C₁₋₂alkylene-OC(O)—C₁₋₆alkyl; and in another embodiment,R⁵ is —C₀₋₃alkylene-SR^(5a), where R^(5a) is —C(O)—R^(5aa), and R^(5aa)is —C₁₋₂alkylene-OC(O)—C₀₋₆alkylenearyl; and in still anotherembodiment, R⁵ is —C₀₋₃alkylene-SR^(5a), where R^(5a) is —C(O)—R^(5aa),and R^(5aa) is —O—C₁₋₂alkylene-OC(O)O—C₁₋₆alkyl, for example, R⁵ can be—CH₂SC(O)—OCH(CH₃)OC(O)OCH(CH₃)₂.

In one embodiment, R⁵ is —C₀₋₃alkylene-C(O)NR^(5b)R^(5c). The R^(5b)moiety is H, —OH, —OC(O)R^(5ba), —CH₂COOH, —O-benzyl, -pyridyl, or—OC(S)NR^(5bb)R^(5bc). R^(5ba) is H, —C₁₋₆alkyl, aryl, —OCH₂-aryl (e.g.,—OCH₂-phenyl), —CH₂O-aryl (e.g., —CH₂O-phenyl), or —NR^(5bb)R^(5bc). TheR^(5bb) and R^(5bc) moieties are independently H or —C₁₋₄alkyl. In oneembodiment, R^(5b) is —OH or —OC(O)R^(5ba), where —R^(5ba) is—C₁₋₆alkyl. R^(5c) is H, —C₁₋₆alkyl, or —C(O)—R^(5ca), where R^(5ca) isH, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, aryl, or heteroaryl. In one particularembodiment, R⁵ is —C₀₋₃alkylene-C(O)NR^(5b)R^(5c) and R^(5c) is H. Inanother embodiment, R⁵ is —C₀₋₃alkylene-C(O)NR^(5b)R^(5c), where R^(5b)is —OH and R^(5c) is H, for example, R⁵ can be —C(O)NH(OH) or—CH₂C(O)NH(OH). In another embodiment, R⁵ is—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), where R^(5b) is —OC(O)R^(5ba), R^(5ba)is —C₁₋₆alkyl, and R^(5c) is H. Thus, examples of R⁵ include—C(O)N[OC(O)CH₃]H and —C(O)N[OC(O)C(CH₃)₃]H. In still anotherembodiment, R⁵ is —C₀₋₃alkylene-C(O)NR^(5b)R^(5c) and both R^(5b) andR^(5c) are H, for example, R⁵ can be —C(O)NH₂. In another embodiment, R⁵is —C₀₋₃alkylene-C(O)NR^(5b)R^(5c), where R^(5b) is —CH₂COOH and R^(5c)is H, for example, R⁵ can be —C(O)N(CH₂COOH)H. In yet anotherembodiment, R⁵ is —C₀₋₃alkylene-C(O)NR^(5b)R^(5c), where R^(5b) is—OC(O)R^(5ba), R^(5ba) is —O—CH₂-aryl or —CH₂—O-aryl, and R^(5c) is H.Thus, examples of R⁵ include —CH₂—C(O)NH[OC(O)OCH₂-phenyl] and—CH₂—C(O)NH[OC(O)—CH₂O-phenyl]. In another embodiment, R⁵ is—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), where R^(5b) is —OC(S)NR^(5bb)R^(5bc),R^(5bb) and R^(5bc) are both —C₁₋₄alkyl, and R^(5c) is H. For example,R⁵ can be —CH₂—C(O)N[OC(S)N(CH₃)₂]H.

In one particular embodiment, R⁵ is selected from —C₀₋₃alkylene-SR^(5a)and —C₀₋₃alkylene-C(O)NR^(5b)R^(5c); where R^(5a) is H or—C(O)—C₁₋₆alkyl; R^(5b) is H, —OH, or —OC(O)—C₁₋₆alkyl; and R^(5c) is Hor —C₁₋₆alkyl.

In one embodiment, R⁵ is —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d). The R^(5d)moiety is H, —C₁₋₄alkyl, —C₀₋₃alkylenearyl, —NR^(5da)R^(5db), —CH₂SH, or—O—C₁₋₆alkyl. The R^(5da) and R^(5db) moieties are independently H or—C₁₋₄alkyl. In one particular embodiment, R⁵ is—C₀₋₃alkylene-NR^(5b)—C(O)R^(5d), where R^(5b) is —OH and R^(5d) is H,for example, R⁵ can be —CH₂—N(OH)C(O)H; and in another embodiment,R^(5b) is —OH and R^(5d) is —C₁₋₄alkyl, for example, R⁵ can be—CH₂—N(OH)C(O)CH₃. In another embodiment, R⁵ is—C₀₋₃alkylene-NR^(5b)—C(O)R^(5d), where R^(5b) is H and R^(5d) is—CH₂SH, for example, R⁵ can be —NHC(O)—CH₂SH or —CH₂NHC(O)—CH₂SH.

In yet another embodiment, R⁵ is —NH—C₀₋₁alkylene-P(O)(OR^(5e))₂. TheR^(5e) moiety is H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl,—C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl, —CH(CH₃)—O—C(O)R^(5ea),

The R^(5ea) group is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(5eb)R^(5ec),or —CH(NH₂)CH₂COOCH₃. R^(5eb) and R^(5ec) are independently H,—C₁₋₄alkyl, or —C₁₋₃alkylenearyl (e.g., benzyl). R^(5eb) and R^(5ec) mayalso be taken together to form —(CH₂)₃₋₆—. In one embodiment, R^(5eb) is—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, where R^(5e) is H, for example, R⁵ canbe —NH—CH₂—P(O)(OH)₂.

In one embodiment, R⁵ is —C₀₋₃alkylene-P(O)OR^(5e)R^(5f). The R^(5f)moiety is H, —C₁₋₄alkyl, —C₀₋₃alkylenearyl,—C₁₋₃alkylene-NR^(5fa)R^(5fb), or—C₁₋₃alkylene(aryl)-C₀₋₃alkylene-NR^(5fa)R^(5fb). The R^(5fa) andR^(5fb) groups are independently H or —C₁₋₄alkyl. In one embodiment,R^(5e) is H, for example, R⁵ can be —C₀₋₃alkylene-P(O)(OH)R^(5f).

In one embodiment, R⁵ is —C₀₋₂alkylene-CHR^(5g)—COOH. The R^(5g) moietyis H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl, or —CH₂—O—(CH₂)₂—OCH₃. In oneparticular embodiment, R^(5g) is —CH₂—O—(CH₂)₂—OCH₃, for example, R⁵ canbe —CH₂—C[CH₂—O—(CH₂)₂—OCH₃]H—COOH. In another embodiment, R^(5g) is H,for example, R⁵ can be —CH₂COOH.

In one embodiment, R⁵ is —C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH. TheR^(5h) moiety is H or —C₁₋₄alkyl. The R^(5i) moiety is H, —C₁₋₄alkyl, or—C₀₋₃alkylenearyl. In one embodiment, R^(5h) is H and R^(5i) is—C₀₋₃alkylenearyl, and the aryl is optionally substituted with 1 to 3substituents such as —OH, for example, R⁵ can be—C(O)NH—CH(CH₂-phenyl-OH)(COOH).

In another embodiment, R⁵ is —C₀₋₃alkylene-S—SR^(5j), and the R^(5j)moiety is —C₁₋₆alkyl, aryl, or —CH₂CH(NH₂)COOH. Examples of such R⁵groups include —C₀₋₃alkylene-S—S—CH₃, —C₀₋₃alkylene-S—S-phenyl, and—C₀₋₃alkylene-S—S—CH₂CH(NH₂)—COOH.

R⁶ is selected from —C₁₋₆alkyl, —CH₂—O—(CH₂)₂OCH₃,—C₁₋₆alkylene-O—C₁₋₆alkyl, —C₀₋₃alkylenearyl, —C₀₋₃alkyleneheteroaryl,and —C₀₋₃alkylene-C₃₋₇cycloalkyl. In one particular embodiment, R⁶ isselected from —C₁₋₆alkyl, —C₀₋₃alkylenearyl, and—C₀₋₃alkylene-C₃₋₇cycloalkyl. Each alkyl and each aryl in R⁶ isoptionally substituted with 1 to 7 fluoro atoms, where the term “alkyl”is intended to include divalent alkylene groups such as those present in—C₁₋₆alkylene-O—C₁₋₆alkyl and —C₀₋₃alkylene-C₃₋₇cycloalkyl, for example.In addition, each aryl and heteroaryl in R⁶ may be substituted with 1 to3 —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, phenyl, —NO₂, —NH₂,—NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)₂ groups. One exemplary substituted R⁶group is —C₀₋₃alkylenearyl, where the aryl is optionally substitutedwith phenyl, for example, R⁶ is —CH₂-biphenyl. Further, each of theaforementioned alkyl, alkenyl and alkynyl groups may be substituted with1 to 5 fluoro atoms.

In one embodiment, R⁶ is —C₁₋₆alkyl, for example, —CH₃, —CH₂CH₃,—CH(CH₃)₂, —(CH₂)₂CH₃, —(CH₂)₃CH₃, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂,—CH₂C(CH₃)₃, —(CH₂)₂CH(CH₃)₂, or —(CH₂)₄CH₃. As noted above, each alkylin R⁶ is optionally substituted with 1 to 7 fluoro atoms. Examples ofsuch fluoro-substituted R⁶ groups include —(CH₂)₂CF₃ and —(CH₂)₃CF₃.

In another embodiment, R⁶ is —CH₂—O—(CH₂)₂OCH₃. In still another oneembodiment, R⁶ is —C₁₋₆alkylene-O—C₁₋₆alkyl, for example, —OCH₃ and—CH₂OCH₃.

In one embodiment, R⁶ is —C₀₋₃alkylenearyl, for example, phenyl, benzyl,—CH₂-biphenyl, —(CH₂)₂-phenyl and —CH₂-naphthalen-1-yl. The aryl may besubstituted with 1 to 3 substituents. Thus, other examples of R⁶ includemono-substituted groups such as, methylbenzyl, chlorobenzyl,fluorobenzyl, fluorophenyl, bromobenzyl, iodobenzyl, -benzyl-CF₃,2-trifluoromethyl-benzyl, -benzyl-CN, and -benzyl-NO₂; anddi-substituted groups such as di-chlorobenzyl and di-fluorobenzyl. Eacharyl may also be substituted with 1 to 7 fluoro atoms. Thus, otherexamples of R⁶ include penta-fluorobenzyl.

In one embodiment, R⁶ is —C₀₋₃alkyleneheteroaryl, for example,—CH₂-pyridyl, —CH₂-furanyl, —CH₂-thienyl, and —CH₂-thiophenyl. Inanother embodiment, R⁶ is —C₀₋₃alkylene-C₃₋₇cycloalkyl, for example,—CH₂-cyclopropyl, cyclopentyl, —CH₂-cyclopentyl, -cyclohexyl, and—CH₂-cyclohexyl.

R⁷ is H or is taken together with R⁶ to form —C₃₋₈cycloalkyl. In oneembodiment, R⁷ is H. In another embodiment, R⁷ is taken together with R⁶to form —C₃₋₈cycloalkyl, for example cyclopentyl.

One particular embodiment of the invention provides for an activecompound of formula I where R⁵ is —C₀₋₃alkylene-SH. One correspondingprodrug (prodrug A) is a dimer form of the compound:

In one particular embodiment, the compound of formula I is the speciesembodied in formula Ia:

where:

Y is:

Q is —C(R³)—, Z is a bond and W is —N—;or

Y is:

Q is —C(R³)—, Z is —C(O)—, and W is —N—;

Ar—X—CR⁵R⁶R⁷ is selected from:

andR¹⁻³, X, and R⁵⁻⁷ are as defined for formula I; and pharmaceuticallyacceptable salts thereof.

In another particular embodiment, the compound of formula I is thespecies embodied in formula Ib:

where R¹⁻³, X, and R⁵⁻⁷ are as defined for formula I; andpharmaceutically acceptable salts thereof. In one particular embodimentof formula Ib: R¹ is —C₁₋₆alkylene-OH or —CHO; R² is H or halo; R³ is—C₁₋₁₀alkyl; X is —SO₂NHC(O)—C₁₋₉alkylene-NHC(O)—; R⁵ is—C₀₋₃alkylene-SH, —C₀₋₃alkylene-C(O)N(R^(5b))H,—NH—C₀₋₁alkylene-P(O)(OH)₂, or—C₀₋₂alkylene-CH[—CH₂—O—(CH₂)₂—OCH₃]—COOH, where R^(5b) is —OH or—OC(O)—C₁₋₆alkyl; R⁶ is —C₁₋₆alkyl or —C₀₋₃alkylenearyl; and R⁷ is H oris taken together with R⁶ to form —C₃₋₈cycloalkyl; where one —CH₂— inthe —C₁₋₉alkylene- portion of X is optionally replaced with a—C₄₋₈cycloalkylene- group; one —CH₂— moiety is optionally replaced witha —NHC(O)— moiety; one —CH₂— moiety is optionally substituted with —COOHor an amino acid side chain; and the aryl in R⁶ is optionallysubstituted with phenyl.

In another particular embodiment, the compound of formula 1 is thespecies embodied in formula Ic:

where R¹⁻³, X, and R⁵⁻⁷ are as defined for formula I; andpharmaceutically acceptable salts thereof. In one particular embodimentof formula Ic: R¹ is —C₁₋₆alkylene-OH, —COOH, —CHO,—C₁₋₃alkylene-NHCH(COOH)(C₁₋₆alkyl), or —C(O)NHCH₂R^(1b), where R^(1b)is —C₀₋₃alkylenearyl or —C₀₋₃alkyleneheteroaryl; R² is halo; R³ is—C₁₋₁₀alkyl; X is —SO₂NHC(O)—C₁₋₉alkylene-NHC(O)—; R⁵ is—C₀₋₃alkylene-SH or —C₀₋₃alkylene-C(O)N(OH)H; R⁶ is —C₁₋₆alkyl or—C₀₋₃alkylenearyl; and R⁷ is H; where one —CH₂— moiety in the—C₁₋₉alkylene- portion of X is optionally replaced with a —NHC(O)—moiety.

In yet another embodiment, the compound of formula I is the speciesembodied in formula Id:

where R³, X, and R⁵⁻⁷ are as defined for formula I; and pharmaceuticallyacceptable salts thereof. In one particular embodiment of formula Id: R³is —C₁₋₁₀alkyl; X is —SO₂NHC(O)— or —SO₂NHC(O)—C₁₋₅alkylene-NHC(O)—; R⁵is —C₀₋₃alkylene-SH or —C₀₋₃alkylene-C(O)N(OH)H; R⁶ is —C₁₋₆alkyl or—C₀₋₃alkylenearyl; and R⁷ is H; where one —CH₂— moiety in the—C₁₋₅alkylene- portion of X is optionally replaced with a —NHC(O)—moiety; and one —CH₂— moiety is optionally substituted with an aminoacid side chain.

In one embodiment of the invention, R¹ is —C₁₋₆alkylene-OH, —COOR^(1a),—CHO, —C₁₋₃alkylene-NHCH(COOH)(C₁₋₆alkyl), or —C(O)NHCH₂R^(1b); whereR^(1a) is H; and R^(1b) is —C₀₋₃alkylenearyl or —C₀₋₃alkyleneheteroaryl;R² is H or halo; R³ is —C₁₋₁₀alkyl; X is —SO₂NHC(O)— or—SO₂NHC(O)—C₁₋₉alkylene-NHC(O)—; R⁵ is —C₀₋₃alkylene-SH,—C₀₋₃alkylene-C(O)N(R^(5b))H, —NH—C₀₋₁alkylene-P(O)(OH)₂, or—C₀₋₂alkylene-CH[—CH₂—O—(CH₂)₂—OCH₃]—COOH; where R^(5b) is —OH or—OC(O)—C₁₋₆alkyl; R⁶ is —C₁₋₆alkyl or —C₀₋₃alkylenearyl; and R⁷ is H oris taken together with R⁶ to form —C₃₋₈cycloalkyl; where one —CH₂— inthe —C₁₋₉alkylene- portion of X is optionally replaced with a—C₄₋₈cycloalkylene- group; one —CH₂— moiety is optionally replaced witha —NHC(O)-moiety; and one —CH₂— moiety is optionally substituted with—COOH or an amino acid side chain; and the aryl in R⁶ is optionallysubstituted with phenyl; and pharmaceutically acceptable salts thereof.In another aspect, this embodiment has formula Ia, Ib, Ic, or Id.

In another embodiment of the invention, R¹ is selected from —CH₂OH,—COOH, —CHO, —CH₂NHCH(COOH)[CH₂CH(CH₃)₂], —C(O)NHCH₂-phenyl,—C(O)NH(CH₂)₂-phenyl, —C(O)NH(CH₂)₃-phenyl, —C(O)NH(CH₂)₄-phenyl,—C(O)NHCH₂-2-thienyl, and —C(O)NH(CH₂)₂-2-thienyl; R² is selected from Hand chloro; R³ is —(CH₂)₃CH₃; X is selected from:

—SO₂NHC(O)—;

—SO₂NHC(O)CH[CH(CH₃)₂]—NHC(O)—;

—SO₂NHC(O)CH₂—NHC(O)—;

SO₂NHC(O)-cyclopentylene-NHC(O)—;

—SO₂NHC(O)-cyclohexylene-NHC(O)—;

—SO₂NHC(O)(CH₂)₂—NHC(O)—;

—SO₂NHC(O)CH₂—NHC(O)—CH₂—NHC(O)—;

—SO₂NHC(O)(CH₂)₄—NHC(O)—;

—SO₂NHC(O)(CH₂)₂—NHC(O)—CH₂—NHC(O)—;

—SO₂—NHC(O)(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—;

—SO₂NHC(O)(CH₂)₂—NHC(O)—CH₂—CH(COOH)—NHC(O)—;

—SO₂—NHC(O)(CH₂)₆—NHC(O)—;

—SO₂NHC(O)(CH₂)₂—NHC(O)—(CH₂)₂—CH(COOH)—NHC(O)—;

—SO₂—NHC(O)(CH₂)₄—NHC(O)—CH₂—NHC(O)—; and

—SO₂NHC(O)(CH₂)₆—NHC(O)—CH₂—NHC(O)—;

R⁵ is selected from —SH, —CH₂—SH, —C(O)NH(OH), —C(O)NH[OC(O)CH₃],—C(O)NH[OC(O)C(CH₃)₃], —NH—CH₂—P(O)(OH)₂, and—CH₂—CH[CH₂—O—(CH₂)₂—OCH₃]—COOH; R⁶ is selected from —CH₃, —CH(CH₃)₂,—CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂-phenyl, and —CH₂-biphenyl; and R⁷ isH or is taken together with R⁶ to form cyclopentyl; and pharmaceuticallyacceptable salts thereof. In another aspect, this embodiment has formulaIa, Ib, Ic, or Id.

In one embodiment, R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f),—C₀₋₂alkylene-CHR^(5g)—COOH, and—C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH; where R^(5a) is H, R^(5b) is—OH, R^(5c) is H, R^(5d) is H, R^(5e) is H; and R^(5f), R^(5g), R^(5h),R^(5i) are as defined for formula I. More particularly, in oneembodiment, R⁵ is selected from —C₀₋₁alkylene-SH,—C₀₋₁alkylene-C(O)—N(OH)H, and —C₀₋₃alkylene-N(OH)—C(O)H. In anotherembodiment, R⁵ is selected from —C₀₋₃alkylene-SR^(5a), and—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), where R^(5a) is H; R^(5b) is —OH. Inone particular embodiment, R^(5c) is H. In another aspect, theseembodiments have formula Ia, Ib, Ic, or Id.

In yet another embodiment, R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f), and—C₀₋₃alkylene-S—SR^(5j); where R^(5a) is —C(O)—R^(5aa); R^(5b) is H,—OC(O)R^(5ba), —CH₂COOH, —O-benzyl, -pyridyl, or —OC(S)NR^(5bb)R^(5bc);R^(5e) is —C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl,—C₃₋₇cycloalkyl, —CH(CH₃)—O—C(O)R^(5ea),

and where R^(5aa), R^(5ba), R^(5bb), R^(5bc), R^(5c), R^(5d), R^(5ea),R^(5f), and R^(5j) are as defined for formula I. In one aspect of theinvention, these compounds may find particular utility as prodrugs or asintermediates in the synthetic procedures described herein. In anotheraspect, these embodiments have formula Ia, Ib, Ic, or Id.

In one particular embodiment, R⁵ is selected from —C₀₋₃alkylene-SR^(5a)and —C₀₋₃alkylene-C(O)NR^(5b)R^(5c); where R^(5a) is H or—C(O)—C₁₋₆alkyl; R^(5b) is H, —OH, or —OC(O)—C₁₋₆alkyl; and R⁵ is H or—C₁₋₆alkyl. In another aspect, this embodiment has formula Ia, Ib, Ic,or Id.

A particular group of compounds of formula I are those disclosed in U.S.Provisional Application No. 61/048,806, filed on Apr. 29, 2008. Thisgroup includes compounds of formula (I′):

wherein:

Y′ is:

Q′ is —C(R³′)—; Z′ is a bond and W′ is —N—, or Z′ is —C(O)— and W′ is—CH—;or Y′ is:

Q′ is —C(R³′)—, Z′ is —C(O)—, and W′ is —N—; R¹′ is selected from—C₁₋₆alkylene-OH, —COOR^(1a), —CHO, —C₁₋₃alkylene-NHCH(COOH)(C₁₋₆alkyl),—C(O)NHCH(COOH)(C₁₋₆alkyl), and —C(O)NHCH₂R^(1b); where R^(1a) isselected from H and —C₁₋₆alkyl; R^(1b) is selected from—C₀₋₃alkylenearyl and —C₀₋₃alkyleneheteroaryl; R²′ is selected from H,—CH₂OH, halo, —NO₂, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, —CN,—C(O)R^(2a), and —C₀₋₃alkylenearyl; where R^(2a) is selected from H,—C₁₋₆alkyl, —C₃₋₆cycloalkyl, —C₀₋₃alkylene-phenyl, —OR^(2b) and—NR^(2c)R^(2d); R^(2b) is selected from H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl,phenyl and benzyl; and R^(2c) and R^(2d) are independently selected fromH, —C₁₋₄alkyl, and —C₀₋₁alkylene-phenyl; R³′ is selected from—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₃₋₁₀alkynyl, —C₀₋₃alkylene-C₃₋₇cycloalkyl, —C₂₋₃alkenylene-C₃₋₇cycloalkyl,—C₂₋₃alkynylene-C₃₋₇cycloalkyl,—C₀₋₅alkylene-NR^(3a)—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-S—C₁₋₅alkylene-R^(3b), and —C₀₋₃alkylenearyl; R^(3a) is H,—C₁₋₆alkyl, —C₃₋₇cycloalkyl, or —C₀₋₃alkylenearyl; and R^(3b) is H,—C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, or aryl; r is0, 1 or 2; Ar′—X′—CR⁵′R⁶′R⁷′ is selected from:

X′ is —SO₂NHC(O)— or —SO₂NHC(O)—C₁₋₁₂alkylene-; R⁵′ is selected from—C₀₋₃alkylene-SR^(5a), —C₀₋₃alkylene-C(O)NR^(5b)R^(5c),—C₀₋₃alkylene-NR^(5b)—C(O)R^(5d), —NH—C₀₋₁alkylene-P(O)(OR^(5e))₂,—C₀₋₃alkylene-P(O)OR^(5e)R^(5f), —C₀₋₂alkylene-CHR^(5g)—COOH,—C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH, and —C₀₋₃alkylene-S—SR^(5j);R^(5a) is H or —C(O)R^(5aa); R^(5aa) is —C₁₋₆alkyl,—C₀₋₆alkylene-C₃₋₇cycloalkyl, —C₀₋₆alkylenearyl,—C₀₋₆alkyleneheteroaryl, —C₀₋₆alkylenemorpholine,—C₀₋₆alkylene-piperazine-CH₃, —CH[N(R^(5ab))₂]-aa where aa is an aminoacid side chain, -2-pyrrolidine, —C₀₋₆alkylene-OR^(5ab),—O—C₀₋₆alkylenearyl, —C₁₋₂alkylene-OC(O)—C₁₋₆alkyl,—C₁₋₂alkylene-OC(O)—C₀₋₆alkylenearyl, or—O—C₁₋₂alkylene-OC(O)O—C₁₋₆alkyl; R^(5ab) is independently H or—C₁₋₆alkyl; R^(5b) is H, —OH, —OC(O)R^(5ba), —CH₂COOH, —O-benzyl,-pyridyl, or —OC(S)NR^(5bb)R^(5bc); R^(5ba) is H, —C₁₋₆alkyl, aryl,—OCH₂-aryl, —CH₂O-aryl, or —NR^(5bb)R^(5bc); R^(5bb) and R^(bc) areindependently selected from H and —C₁₋₄alkyl; R^(5c) is H, —C₁₋₆alkyl,or —C(O)—R^(5ca); R^(5ca) is H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, aryl, orheteroaryl; R^(5d) is H, —C₁₋₄alkyl, —C₀₋₃alkylenearyl,—NR^(5da)R^(5db), —CH₂SH, or —O—C₁₋₆alkyl; R^(5da) and R^(5db) areindependently selected from H and —C₁₋₄alkyl; R^(5e) is H, —C₁₋₆alkyl,—C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl, —CH(CH₃)—O—C(O)R^(5ea),

R^(5ea) is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(5eb)R^(5ec), or—CH(NH₂)CH₂COOCH₃; R^(5eb) and R^(5ec) are independently selected fromH, —C₁₋₄alkyl, and —C₁₋₃alkylenearyl, or are taken together as—(CH₂)₃₋₆—; R^(5f) is H, —C₁₋₄alkyl, —C₀₋₃alkylenearyl,—C₁₋₃alkylene-NR^(5fa)R^(5fb), or—C₁₋₃alkylene(aryl)-C₀₋₃alkylene-NR^(5fa)R^(5fb); R^(5fa) and R^(5fb)are independently selected from H and —C₁₋₄alkyl; R^(5g) is H,—C₁₋₃alkylenearyl, or —CH₂—O—(CH₂)₂—OCH₃; R^(5h) is H or —C₁₋₄alkyl;R^(5i) is H, —C₁₋₄alkyl, or —C₀₋₃alkylenearyl; and R^(5j) is —C₁₋₆alkyl,aryl, or —CH₂CH(NH₂)COOH; R⁶′ is selected from —C₁₋₆alkyl,—CH₂—O—(CH₂)₂—OCH₃, —C₁₋₆alkylene-O—C₁₋₆alkyl, —C₀₋₃alkylenearyl,—C₀₋₃alkyleneheteroaryl, and —C₀₋₃alkylene-C₃₋₇cycloalkyl; and R⁷′ is Hor is taken together with R⁶ to form —C₃₋₈cycloalkyl; wherein: each—CH₂— group in —(CH₂)_(r)— is optionally substituted with 1 or 2substituents independently selected from —C₁₋₄alkyl and fluoro; one—CH₂— in the —C₁₋₁₂alkylene- portion of X′ is optionally replaced with—C₄₋₈cycloalkylene-; one or more —CH₂— moieties are optionally replacedwith a —NR⁴′—C(O)— or —C(O)—NR⁴′— moiety, where R⁴′ is selected from H,—OH, and —C₁₋₄alkyl; and one or more —CH₂— moieties are optionallysubstituted with —COOH or an amino acid side chain; each alkyl and eacharyl in is optionally substituted with 1 to 7 fluoro atoms; each ring inAr′—X′—CR⁵′R⁶′R⁷′ and each aryl and heteroaryl in R¹′, R²′, R³′, andR⁵′⁻⁶′ is optionally substituted with 1 to 3 substituents independentlyselected from —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo,—O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, -phenyl,—NO₂, —NH₂, —NH—C₁₋₆alkyl and —N(C₁₋₆alkyl)₂, wherein each alkyl,alkenyl and alkynyl is optionally substituted with 1 to 5 fluoro atoms;and pharmaceutically acceptable salts thereof.

In addition, compounds of formula I that are of particular interestinclude those set forth in the Examples below, as well as thepharmaceutically acceptable salts thereof.

Definitions

When describing the compounds, compositions, methods and processes ofthe invention, the following terms have the meanings set forth below,unless indicated otherwise. Additionally, as used herein, the singularforms “a,” “an,” and “the” include the corresponding plural forms unlessthe context of use clearly dictates otherwise. The terms “comprising”,“including,” and “having” are intended to be inclusive and mean thatthere may be additional elements other than the listed elements. Allnumbers expressing quantities of ingredients, properties such asmolecular weight, reaction conditions, and so forth used herein are tobe understood as being modified in all instances by the term “about,”unless otherwise indicated. Accordingly, the numbers set forth hereinare approximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At least, and not as anattempt to limit the application of the doctrine of equivalents to thescope of the claims, each number should at least be construed in lightof the reported significant digits and by applying ordinary roundingtechniques.

The term “alkyl” means a monovalent saturated hydrocarbon group whichmay be linear or branched. Unless otherwise defined, such alkyl groupstypically contain from 1 to 10 carbon atoms and include, for example,—C₁₋₄alkyl, —C₁₋₆alkyl, and —C₁₋₁₀alkyl. Representative alkyl groupsinclude, by way of example, methyl, ethyl, n-propyl, isopropyl, n-butyl,s-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl and the like.

When a specific number of carbon atoms is intended for a particular termused herein, the number of carbon atoms is shown preceding the term assubscript. For example, the term “—C₁₋₆alkyl” means an alkyl grouphaving from 1 to 6 carbon atoms, and the term “—C₃₋₇ cycloalkyl” means acycloalkyl group having from 3 to 7 carbon atoms, respectively, wherethe carbon atoms are in any acceptable configuration.

The term “alkylene” means a divalent saturated hydrocarbon group thatmay be linear or branched. Unless otherwise defined, such alkylenegroups typically contain from 0 to 12 carbon atoms and include, forexample, —C₀₋₁alkylene-, —C₀₋₂alkylene-, —C₀₋₃alkylene-, —C₀₋₅alkylene-,—C₀₋₆alkylene-, —C₁₋₂alkylene- and —C₁₋₁₂alkylene-. Representativealkylene groups include, by way of example, methylene, ethane-1,2-diyl(“ethylene”), propane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl and the like. It is understood that when the alkyleneterm include zero carbons such as —C₀₋₁alkylene- or —C₀₋₅alkylene-, suchterms are intended to include the absence of carbon atoms, that is, thealkylene group is not present except for a covalent bond attaching thegroups separated by the alkylene term.

The term “alkylthio” means a monovalent group of the formula —S-alkyl,where alkyl is as defined herein. Unless otherwise defined, suchalkylthio groups typically contain from 1 to 10 carbon atoms andinclude, for example, —S—C₁₋₄alkyl and —S—C₁₋₆alkyl. Representativealkylthio groups include, by way of example, ethylthio, propylthio,isopropylthio, butylthio, s-butylthio and t-butylthio.

The term “alkenyl” means a monovalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one, andtypically 1, 2 or 3, carbon-carbon double bonds. Unless otherwisedefined, such alkenyl groups typically contain from 2 to 10 carbon atomsand include, for example, —C₂₋₄alkenyl and —C₂₋₁₀alkenyl. Representativealkenyl groups include, by way of example, ethenyl, n-propenyl,isopropenyl, n-but-2-enyl, n-hex-3-enyl and the like. The term“alkenylene” means a divalent alkenyl group, and includes groups such as—C₂₋₃alkenylene-.

The term “alkoxy” means a monovalent group of the formula —O-alkyl,where alkyl is as defined herein. Unless otherwise defined, such alkoxygroups typically contain from 1 to 10 carbon atoms and include, forexample, —O—C₁₋₄alkyl and —O—C₁₋₆alkyl. Representative alkoxy groupsinclude, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, sec-butoxy, isobutoxy, t-butoxy and the like.

The term “alkynyl” means a monovalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one, andtypically 1, 2 or 3, carbon-carbon triple bonds. Unless otherwisedefined, such alkynyl groups typically contain from 2 to 10 carbon atomsand include, for example, —C₂₋₄alkynyl and —C₃₋₁₀alkynyl. Representativealkynyl groups include, by way of example, ethynyl, n-propynyl,n-but-2-ynyl, n-hex-3-ynyl and the like. The term “alkynylene” means adivalent alkynyl group and includes groups such as —C₂₋₃alkynylene-.

Amino acid residues are often designated as —C(O)—CHR—NH—, where the Rmoiety is referred to as the “amino acid side chain.” Thus, for theamino acid valine, HO—C(O)—CH[—CH(CH₃)₂]—NH₂, the side chain is—CH(CH₃)₂. The term “amino acid side chain” is intended to include sidechains of the twenty common naturally occurring amino acids: alanine,arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine,glycine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, proline, serine, threonine, tryptophan, tyrosine, andvaline. Of particular interest are the side chains of non-polar aminoacids such as isoleucine, leucine, and valine.

The term “aryl” means a monovalent aromatic hydrocarbon having a singlering (e.g., phenyl) or fused rings. Fused ring systems include thosethat are fully unsaturated (e.g., naphthalene) as well as those that arepartially unsaturated (e.g., 1,2,3,4-tetrahydronaphthalene). Unlessotherwise defined, such aryl groups typically contain from 6 to 10carbon ring atoms and include, for example, —C₆₋₁₀aryl. Representativearyl groups include, by way of example, phenyl and naphthalene-1-yl,naphthalene-2-yl, and the like. The term “arylene” means a divalent arylgroup such as phenylene.

The term “cycloalkyl” means a monovalent saturated carbocyclichydrocarbon group. Unless otherwise defined, such cycloalkyl groupstypically contain from 3 to 10 carbon atoms and include, for example,—C₃₋₅cycloalkyl, —C₃₋₆cycloalkyl and —C₃₋₇cycloalkyl. Representativecycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like. The term “cycloalkylene” means adivalent aryl group such as —C₄₋₈cycloalkylene.

The term “halo” means fluoro, chloro, bromo and iodo.

As used herein, the phrase “having the formula” or “having thestructure” is not intended to be limiting and is used in the same waythat the term “comprising” is commonly used.

The term “heteroaryl” means a monovalent aromatic group having a singlering or two fused rings and containing in the ring(s) at least oneheteroatom (typically 1 to 3 heteroatoms) selected from nitrogen, oxygenor sulfur. Unless otherwise defined, such heteroaryl groups typicallycontain from 5 to 10 total ring atoms and include, for example,—C₂₋₉heteroaryl. Representative heteroaryl groups include, by way ofexample, monovalent species of pyrrole, imidazole, thiazole, oxazole,furan, thiophene, triazole, pyrazole, isoxazole, isothiazole, pyridine,pyrazine, pyridazine, pyrimidine, triazine, indole, benzofuran,benzothiophene, benzoimidazole, benzthiazole, quinoline, isoquinoline,quinazoline, quinoxaline and the like, where the point of attachment isat any available carbon or nitrogen ring atom.

The term “optionally substituted” means that group in question may beunsubstituted or it may be substituted one or several times, such as 1to 3 times or 1 to 5 times. For example, an alkyl group that is“optionally substituted” with 1 to 5 fluoro atoms, may be unsubstituted,or it may contain 1, 2, 3, 4, or 5 fluoro atoms.

The term “pharmaceutically acceptable” refers to a material that is notbiologically or otherwise unacceptable when used in the invention. Forexample, the term “pharmaceutically acceptable carrier” refers to amaterial that can be incorporated into a composition and administered toa patient without causing unacceptable biological effects or interactingin an unacceptable manner with other components of the composition. Suchpharmaceutically acceptable materials typically have met the requiredstandards of toxicological and manufacturing testing, and include thosematerials identified as suitable inactive ingredients by the U.S. Foodand Drug administration.

The term “pharmaceutically acceptable salt” means a salt prepared from abase or an acid which is acceptable for administration to a patient,such as a mammal (e.g., salts having acceptable mammalian safety for agiven dosage regime). However, it is understood that the salts coveredby the invention are not required to be pharmaceutically acceptablesalts, such as salts of intermediate compounds that are not intended foradministration to a patient. Pharmaceutically acceptable salts can bederived from pharmaceutically acceptable inorganic or organic bases andfrom pharmaceutically acceptable inorganic or organic acids. Inaddition, when a compound of formula I contains both a basic moiety,such as an amine, pyridine or imidazole, and an acidic moiety such as acarboxylic acid or tetrazole, zwitterions may be formed and are includedwithin the term “salt” as used herein. Salts derived frompharmaceutically acceptable inorganic bases include ammonium, calcium,copper, ferric, ferrous, lithium, magnesium, manganic, manganous,potassium, sodium, and zinc salts, and the like. Salts derived frompharmaceutically acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. Salts derived frompharmaceutically acceptable inorganic acids include salts of boric,carbonic, hydrohalic (hydrobromic, hydrochloric, hydrofluoric orhydroiodic), nitric, phosphoric, sulfamic and sulfuric acids. Saltsderived from pharmaceutically acceptable organic acids include salts ofaliphatic hydroxyl acids (e.g., citric, gluconic, glycolic, lactic,lactobionic, malic, and tartaric acids), aliphatic monocarboxylic acids(e.g., acetic, butyric, formic, propionic and trifluoroacetic acids),amino acids (e.g., aspartic and glutamic acids), aromatic carboxylicacids (e.g., benzoic, p-chlorobenzoic, diphenylacetic, gentisic,hippuric, and triphenylacetic acids), aromatic hydroxyl acids (e.g.,o-hydroxybenzoic, p-hydroxybenzoic, 1-hydroxynaphthalene-2-carboxylicand 3-hydroxynaphthalene-2-carboxylic acids), ascorbic, dicarboxylicacids (e.g., fumaric, maleic, oxalic and succinic acids), glucoronic,mandelic, mucic, nicotinic, orotic, pamoic, pantothenic, sulfonic acids(e.g., benzenesulfonic, camphosulfonic, edisylic, ethanesulfonic,isethionic, methanesulfonic, naphthalenesulfonic,naphthalene-1,5-disulfonic, naphthalene-2,6-disulfonic andp-toluenesulfonic acids), xinafoic acid, and the like.

As used herein, the term “prodrug” is intended to mean an inactive (orsignificantly less active) precursor of a drug that is converted intoits active form in the body under physiological conditions, e.g., bynormal metabolic processes. The term is also intended to include certainprotected derivatives of compounds of formula I that may be made priorto a final deprotection stage. Such compounds may not possesspharmacological activity at AT₁ and/or NEP, but may be administeredorally or parenterally and thereafter metabolized in the body to formcompounds of the invention which are pharmacologically active at AT₁and/or NEP. Thus, all protected derivatives and prodrugs of compoundsformula I are included within the scope of the invention. Prodrugs ofcompounds of formula I having a free carboxyl, sulfhydryl or hydroxygroup can be readily synthesized by techniques that are well known inthe art. These prodrug derivatives are then converted by solvolysis orunder physiological conditions to be the free carboxyl, sulfhydryland/or hydroxy compounds. Exemplary prodrugs include: esters includingC₁₋₆alkylesters and aryl-C₁₋₆alkylesters, carbonate esters, hemi-esters,phosphate esters, nitro esters, sulfate esters, sulfoxides, amides,carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals,ketals, and disulfides. In one embodiment, the compounds of formula Ihave a free sulfhydryl or a free carboxyl and the prodrug is an esterderivative.

The term “protected derivatives thereof” means a derivative of thespecified compound in which one or more functional groups of thecompound are protected or blocked from undergoing undesired reactionswith a protecting or blocking group. Functional groups that may beprotected include, by way of example, carboxy groups, amino groups,hydroxyl groups, thiol groups, carbonyl groups and the like.Representative protecting groups for carboxy groups include esters (suchas a p-methoxybenzyl ester), amides and hydrazides; for amino groups,carbamates (such as t-butoxycarbonyl) and amides; for hydroxyl groups,ethers and esters; for thiol groups, thioethers and thioesters; forcarbonyl groups, acetals and ketals; and the like. Such protectinggroups are well known to those skilled in the art and are described, forexample, in T. W. Greene and G. M. Wuts, Protective Groups in OrganicSynthesis, Third Edition, Wiley, New York, 1999, and references citedtherein.

The term “solvate” means a complex or aggregate formed by one or moremolecules of a solute, e.g., a compound of formula I or apharmaceutically acceptable salt thereof, and one or more molecules of asolvent. Such solvates are typically crystalline solids having asubstantially fixed molar ratio of solute and solvent. Representativesolvents include, by way of example, water, methanol, ethanol,isopropanol, acetic acid and the like. When the solvent is water, thesolvate formed is a hydrate.

The term “therapeutically effective amount” means an amount sufficientto effect treatment when administered to a patient in need thereof,i.e., the amount of drug needed to obtain the desired therapeuticeffect. For example, a therapeutically effective amount for treatinghypertension is an amount of compound needed to, for example, reduce,suppress, eliminate or prevent the symptoms of hypertension, or to treatthe underlying cause of hypertension. In one embodiment, atherapeutically effective amount is that amount needed to reduce bloodpressure or the amount needed to maintain normal blood pressure. On theother hand, the term “effective amount” means an amount sufficient toobtain a desired result, which may not necessarily be a therapeuticresult. For example, when studying a system comprising an AT₁ receptor,an “effective amount” may be the amount needed to antagonize thereceptor.

The term “treating” or “treatment” as used herein means the treating ortreatment of a disease or medical condition (such as hypertension) in apatient, such as a mammal (particularly a human) that includes one ormore of the following: (a) preventing the disease or medical conditionfrom occurring, such as by prophylactic treatment of a patient; (b)ameliorating the disease or medical condition such as by eliminating orcausing regression of the disease or medical condition in a patient; (c)suppressing the disease or medical condition such as by slowing orarresting the development of the disease or medical condition in apatient; or (d) alleviating the symptoms of the disease or medicalcondition in a patient. For example, the term “treating hypertension”would include preventing hypertension from occurring, amelioratinghypertension, suppressing hypertension, and alleviating the symptoms ofhypertension (e.g., lowering blood pressure). The term “patient” isintended to include those mammals, such as humans, that are in need oftreatment or disease prevention or that are presently being treated fordisease prevention or treatment of a specific disease or medicalcondition, as well as test subjects in which compounds of the inventionare being evaluated or being used in a assay, for example an animalmodel.

All other terms used herein are intended to have their ordinary meaningas understood by those of ordinary skill in the art to which theypertain.

General Synthetic Procedures

Compounds of the invention can be prepared from readily availablestarting materials using the following general methods, the proceduresset forth in the Examples, or by using other methods, reagents, andstarting materials that are known to those of ordinary skill in the art.Although the following procedures may illustrate a particular embodimentof the invention, it is understood that other embodiments of theinvention can be similarly prepared using the same or similar methods orby using other methods, reagents and starting materials known to thoseof ordinary skill in the art. It will also be appreciated that wheretypical or preferred process conditions (e.g., reaction temperatures,times, mole ratios of reactants, solvents, pressures, etc.) are given,other process conditions can also be used unless otherwise stated. Whileoptimum reaction conditions will typically vary depending on variousreaction parameters such as the particular reactants, solvents andquantities used, those of ordinary skill in the art can readilydetermine suitable reaction conditions using routine optimizationprocedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary or desired to preventcertain functional groups from undergoing undesired reactions. Thechoice of a suitable protecting group for a particular functional groupas well as suitable conditions and reagents for protection anddeprotection of such functional groups are well known in the art.Protecting groups other than those illustrated in the proceduresdescribed herein may be used, if desired. For example, numerousprotecting groups, and their introduction and removal, are described inT. W. Greene and G. M. Wuts, Protective Groups in Organic Synthesis,supra. More specifically, the following abbreviations and reagents areused in the schemes presented below:

P¹ represents an “amino-protecting group,” a term used herein to mean aprotecting group suitable for preventing undesired reactions at an aminogroup. Representative amino-protecting groups include, but are notlimited to, t-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl(Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS),t-butyldimethylsilyl (TBDMS), and the like. Standard deprotectiontechniques are used to remove the P^(i) group. For example, an N—BOCgroup can be removed using an acidic reagent such as TFA in DCM or HClin 1,4-dioxane, while a Cbz group can be removed by employing catalytichydrogenation conditions such as H₂ (1 atm) and 10% Pd/C in an alcoholicsolvent (“H₂/Pd/C”).

P² represents a “carboxy-protecting group,” a term used herein to mean aprotecting group suitable for preventing undesired reactions at acarboxy group. Representative carboxy-protecting groups include, but arenot limited to, methyl, ethyl, t-butyl, benzyl (Bn), p-methoxybenzyl(PMB), 9-fluorenylmethyl (Fm), trimethylsilyl (TMS),t-butyldimethylsilyl (TBDMS), diphenylmethyl (benzhydryl, DPM) and thelike. Standard deprotection techniques and reagents are used to removethe P² group, and may vary depending upon which group is used. Forexample, NaOH is commonly used when P² is methyl, an acid such as TFA orHCl is commonly used when P² is t-butyl, and H₂/Pd/C may be used when P²is benzyl.

P³ represents a “thiol-protecting group,” a term used herein to mean aprotecting group suitable for preventing undesired reactions at a thiolgroup. Representative thiol-protecting groups include, but are notlimited to, ethers, esters such as —C(O)CH₃, and the like. Standarddeprotection techniques and reagents such as NaOH, primary alkylamines,and hydrazine, may be used to remove the P³ group.

P⁵ represents a “hydroxyl-protecting group,” a term used herein to meana protecting group suitable for preventing undesired reactions at ahydroxyl group. Representative hydroxyl-protecting groups include, butare not limited to alkyl groups such as t-butyl, silyl groups includingtriC₁₋₆alkylsilyl groups, such as trimethylsilyl (TMS), triethylsilyl(TES), and tert-butyldimethylsilyl (TBDMS); esters (acyl groups)including C₁₋₆alkanoyl groups, such as formyl, acetyl, and pivaloyl, andaromatic acyl groups such as benzoyl; arylmethyl groups such as benzyl(Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl(benzhydryl, DPM); and the like. Standard deprotection techniques andreagents are used to remove the P⁵ group, and may vary depending uponwhich group is used. For example, H₂/Pd/C is commonly used when P⁵ isbenzyl, while NaOH is commonly used when P⁵ is an acyl group.

P⁶ represents a “sulfonamide-protecting group,” a term used herein tomean a protecting group suitable for preventing undesired reactions at asulfonamide group. Representative sulfonamide-protecting groups include,but are not limited to t-butyl and acyl groups. Exemplary acyl groupsinclude aliphatic lower acyl groups such as the formyl, acetyl,phenylacetyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloylgroups, and aromatic acyl groups such as the benzoyl and4-acetoxybenzoyl. Standard deprotection techniques and reagents are usedto remove the P⁶ group, and may vary depending upon which group is used.For example, HCl is commonly used when P⁶ is t-butyl, while NaOH iscommonly used when P⁶ is an acyl group.

P⁷ represents a “phosphate-protecting group or phosphinate-protectinggroup,” a term used herein to mean a protecting group suitable forpreventing undesired reactions at a phosphate or phosphinate group.Representative phosphate and phosphinate protecting groups include, butare not limited to C₁₋₄alkyl, aryl (e.g., phenyl) and substituted aryls(e.g., chlorophenyl and methylphenyl). The protected group can berepresented by —P(O)(OR)₂, where R is a group such as a C₁₋₆alkyl orphenyl. Standard deprotection techniques and reagents such asTMS-I/2,6-lutidine and H₂/Pd/C are used to remove the P⁷ group such asethyl, and benzyl, respectively.

In addition, L and L′ are used to designate a “leaving group,” a termused herein to mean a functional group or atom which can be displaced byanother functional group or atom in a substitution reaction, such as anucleophilic substitution reaction. By way of example, representativeleaving groups include chloro, bromo and iodo groups; sulfonic estergroups, such as mesylate, triflate, tosylate, brosylate, nosylate andthe like; acyloxy groups, such as acetoxy, trifluoroacetoxy; formylgroups; and so forth.

Suitable bases for use in these schemes include, by way of illustrationand not limitation, potassium carbonate, calcium carbonate, sodiumcarbonate, triethylamine, pyridine, 1,8-diazabicyclo-[5.4.0]undec-7-ene(DBU), N,N-diisopropylethylamine (DIPEA), sodium hydroxide, potassiumhydroxide, potassium t-butoxide, and metal hydrides.

Suitable inert diluents or solvents for use in these schemes include, byway of illustration and not limitation, tetrahydrofuran (THF),acetonitrile (MeCN), N,N-dimethylformamide (DMF), dimethyl sulfoxide(DMSO), toluene, dichloromethane (DCM), chloroform (CHCl₃), carbontetrachloride (CCl₄), 1,4-dioxane, methanol, ethanol, water, and thelike.

Suitable carboxylic acid/amine coupling reagents includebenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate(PyBOP), O-(7-azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), N,N′-dicyclohexyl-carbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),N,N-carbonyldiimidazole (CDI), and the like. Coupling reactions areconducted in an inert diluent in the presence of a base, and areperformed under conventional amide bond-forming conditions.

All reactions are typically conducted at a temperature within the rangeof about −78° C. to 100° C., for example at room temperature. Reactionsmay be monitored by use of thin layer chromatography (TLC), highperformance liquid chromatography (HPLC), and/or LCMS until completion.Reactions may be complete in minutes, or may take hours, typically from1-2 hours and up to 48 hours. Upon completion, the resulting mixture orreaction product may be further treated in order to obtain the desiredproduct. For example, the resulting mixture or reaction product may besubjected to one or more of the following procedures: concentrating orpartitioning (e.g., between EtOAc and water or between 5% THF in EtOAcand 1M phosphoric acid); extraction (e.g., with EtOAc, CHCl₃, DCM,chloroform); washing (e.g., with saturated aqueous NaCl, saturatedNaHCO₃, Na₂CO₃ (5%), CHCl₃ or 1M NaOH); drying (e.g., over MgSO₄, overNa₂SO₄, or in vacuo); filtering; crystallizing (e.g., from EtOAc andhexane); being concentrated (e.g., in vacuo); and/or purification (e.g.,silica gel chromatography, flash chromatography, preparative HPLC,reverse phase-HPLC, or crystallization).

By way of illustration, compounds of formula I, as well as their salts,solvates, and prodrugs can be prepared by one or more of the followingexemplary processes.

Peptide Coupling Reaction and Optional Deprotection-Amide Containing “X”Group

Scheme I can be used to prepare compound of the invention where X is—SO₂NHC(O)—C₁₋₁₂alkylene-NHC(O)—, —SO₂NHC(O)—C₁₋₁₂alkylene-C(O)NH—,—C(O)NH—SO₂—C₁₋₁₂alkylene-NHC(O)—, —C(O)NH—SO₂—C₁₋₁₂alkylene-C(O)NH—,—SO₂NHC(O)NH—C₁₋₁₂alkylene-NHC(O)—, —SO₂NHC(O)NH—C₁₋₁₂alkylene-C(O)NH—,—NH—SO₂—NHC(O)—C₁₋₁₂alkylene-NHC(O)—, or—NH—SO₂—NHC(O)—C₁₋₁₂alkylene-C(O)NH—. Thus, since X contains one or moreamide groups, the compounds of the invention may be formed by a couplingreaction under conventional amide bond-forming conditions, followed by adeprotection step if needed. In Scheme I (illustrated for—SO₂NHC(O)—C₁₋₁₂alkylene-NHC(O)— or —SO₂NHC(O)—C₁₋₁₂alkylene-C(O)NH—),the A and B moieties couple to form —NR⁴—C(O)—, —NHC(O)—, —C(O)—NR⁴—, or—C(O)NH— and the sum of a and b is in the range of 1 to 12. Thus, onemoiety comprises an amine group and one moiety comprises a carboxylicacid group, i.e., A is —NH₂ and B is —COOH or A is —COOH and B is —NH₂.

For example, to synthesize a compound of formula I where X contains a—C(O)—NR⁴ group or ends with a —CONH— group, A would be —COOH and Bwould be —NH₂. Similarly, to synthesize a compound of formula I where Xcontains a —NR⁴—C(O)— group or ends with a —NHC(O)— group, A would be—NH₂ and B would be —COOH, which couple to form. A and B can be readilymodified if a longer X is desired or if additional amide groups aredesired. For example, A as —CH₂NH₂ and B as —COOH would couple to form—CH₂NHCO—. It is understood that the carbon atoms in the —(CH₂)_(a) and—(CH₂)_(b) groups make up the X linker. Therefore, one —CH₂— group in—(CH₂)_(a) or —(CH₂)_(b) may be replaced with a —C₄₋₈cycloalkylene-group.

R⁵* may represent R⁵ as defined herein, or a protected form of R⁵ (e.g.,—C(O)—NH(O—P⁵) such as —C(O)—NH(O—C(O)—C₁₋₆alkyl). Therefore, when R⁵*represents R⁵, the reaction is complete after the coupling step.

On the other hand, when R⁵* represents a protected form of R⁵, asubsequent deprotection step would yield the non-protected compound.Reagents and conditions for the deprotection vary with the nature ofprotecting groups in the compound. Typical deprotection conditions whenR⁵* represents —C₀₋₃alkylene-S—P³, include treating the compound withNaOH in an alcoholic solvent at 0° C. or room temperature to yield thenon-protected compound. Typical deprotection conditions when R⁵*represents —C₀₋₃alkylene-C(O)NH(O—P⁵), where P⁵ refers to an acyl groupsuch as —C(O)CH₃, include treating the compound with NaOH at roomtemperature to yield the non-protected compound. Thus, one method ofpreparing compounds of the invention involves coupling compounds (1) and(2), with an optional deprotection step when R⁵* is a protected form ofR⁵, thus forming a compound of formula I or a pharmaceuticallyacceptable salt thereof.

Examples of compound (1) include:4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonicacid (2-aminoacetyl)amide andN-(2-Aminoacetyl)-4-(2-butyl-4-chloro-5-formyl-imidazol-1-ylmethyl)benzenesulfonamide.

Examples of compound (2) include: N-acetoxy-2-benzyl-malonamic acid.

Compound (1)

Compound (1) can be prepared by the following reaction, depicted, forpurposes of illustration, for those compounds where Y is:

Z is a bond; Q is —C(R³)—, W is —N—, R¹ is —CH₂OH, and X is —SO₂NHC(O)—or —SO₂NHC(O)—C₁₋₁₂alkylene-NHC(O)—:

Compounds (1a) and (1b) are combined with K₂CO₃ in a solvent such as DMFto form intermediate (1c), and the amine is then deprotected with TFA toform (1d). Intermediate (1d) is coupled with a compound of formulaP¹—NH—(CH₂)_(a)—COOH, such as N-α-(t-butoxycarbonyl)glycine, in thepresence of a coupling agent such as N,N-carbonyldiimidazole, to form(1e). Intermediate (1e) is reduced with a reducing agent such as sodiumborohydride to form (1f), and the amine is then deprotected with TFA toform Compound (1) where A is —NH(R⁴).

Compound (1a)

Compound (1a) can be readily prepared by techniques that are well knownin the art and/or is commercially available. Examples of compound (1a)include 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde.

Compound (1b)

Compound (1b) can be readily prepared by techniques that are well knownin the art and/or is commercially available. For example, illustratedfor those embodiments where X is —SO₂NHC(O)— or—SO₂NHC(O)—C₁₋₁₂alkylene-NHC(O)—, a solution of compound (1g) (where Land L′ are leaving groups) in a solvent such as DCM can be reacted withNH₂—P⁶ in DIPEA and DCM to form compound (1b). Examples of compound (1g)include 4-bromomethylbenzenesulfonyl chloride (where L is Br, L′ is Cl,and Ar is phenyl) and examples of compound NH₂—P⁶ include t-butyl amine(where P⁶ is t-butyl). Examples of compound (1b) include4′-bromomethyl-biphenyl-2-sulfonic acid t-butylamide and4-bromomethyl-N-t-butylbenzenesulfonamide. Embodiments where X is—SO₂NHC(O)—C₁₋₁₂alkylene-C(O)NH—, —C(O)NH—SO₂—C₁₋₁₂alkylene-NHC(O)—,—C(O)NH—SO₂—C₁₋₁₂alkylene-C(O)NH—, —SO₂NHC(O)NH—C₁₋₁₂alkylene-NHC(O)—,—SO₂NHC(O)NH—C₁₋₁₂alkylene-C(O)NH—,—NH—SO₂—NHC(O)—C₁₋₁₂alkylene-NHC(O)—, or—NH—SO₂—NHC(O)—C₁₋₁₂alkylene-C(O)NH—, can also be prepared by techniquesthat are well known in the art and/or are commercially available.

Compound (2)

Compound (2) is readily synthesized by following the techniquesdescribed in the literature, for example, Neustadt et al. (1994). J.Med. Chem. 37:2461-2476 and Moree et al. (1995) J. Org. Chem. 60:5157-69, as well as by using the exemplary procedures described below.Examples of Compound (2), depicted without chirality, include:

Since compound (2) has a chiral center, it may be desirable tosynthesize a particular stereoisomer, and examples are provided asfollows.

Preparation of Chiral Amino Hydroxamate Compound (2^(i))

A base such as DIPEA and a coupling agent such as EDC are added to asolution of compound (2a) in DMF containing HOBt and hydroxylaminehydrochloride. The mixture is stirred at room temperature untilcompletion (˜12 hours), then concentrated in vacuo. The resultingmaterial is distributed between 5% THF in ethyl acetate and 1Mphosphoric acid. The organic layer is collected and washed with a basesuch as 1M NaOH. The alkaline aqueous layer is then acidified, forexample with 1M phosphoric acid, and extracted with ethyl acetate. Theorganic layer is evaporated and the residue purified by silica gelchromatography to afford compound (2^(i)). Examples of compound (2a)include (R)-3-t-butoxycarbonylamino-4-phenylbutyric acid.

Preparation of Chiral Amino Sulfhydryl Dimer Compound (2^(ii))

Diisopropyl azodicarboxylate is added to a solution oftriphenylphosphine in a solvent such as THF, cooled in an ice bath. Thesolution is stirred and compound (2b) and thioacetic acid are added. Themixture is stirred at 0° C. for 1 hour, then stirred at room temperatureuntil completion (˜12 hours). The mixture is stripped, diluted withethyl acetate, and washed with a cold saturated NaHCO₃ solution. Theorganic layer is dried over MgSO₄, and the filtrate evaporated todryness. The resulting material is flash chromatographed to providecompound (2c). Compound (2c) is dissolved in solvent, followed by theaddition of a base such as 1M LiOH. Air is bubbled through the solutionfor 1 hour followed by the addition of solvent. The reaction is stirredat room temperature until completion (˜24 hours). The solution is thenacidified to pH-5, for example with acetic acid. The precipitate isfiltered and rinsed with deionized water, producing the compound (2d)dimer. The solid is suspended in MeCN, then concentrated under reducedpressure. The recovered material is dissolved in 4M HCl in 1,4-dioxaneand stirred at room temperature until the reaction is complete (˜2hours). The reaction is then concentrated under reduced pressure, andtriturated with ethyl acetate. The product is filtered, washed withethyl acetate, and dried in vacuo to provide compound (2^(ii)). Examplesof compound (2b) include ((R)-1-benzyl-2-hydroxyethyl)carbamic acidt-butyl ester.

Preparation of Chiral Sulfanyl Acid Compound (2^(iii))

Compound (2e) is formed by dissolving a compound such as D-leucine (forR⁶=isobutyl, for example) in 3M HBr (aqueous) and cooled to 0° C. Asolution of NaNO₂ in water is added, and the reaction stirred at 0° C.until completion (˜2.5 hours). The reaction is then extracted with ethylacetate, washed with saturated aqueous NaCl, dried over MgSO₄, filtered,and concentrated to afford compound (2e). Compound (2e) is combined withpotassium thioacetate or sodium thioacetate and DMF, and the reactionstirred at room temperature until completion (˜1 hour). Water is added.The reaction is then extracted with ethyl acetate, washed with saturatedaqueous NaCl, dried over MgSO₄, filtered, and concentrated to providecompound (2^(iii)). The product is purified by silica gelchromatography. Examples of compound (2e) include(R)-2-bromo-4-methylpentanoic acid. Examples of compound (2^(iii))include (S)-2-acetylsulfanyl-4-methylpentanoic acid.

Preparation of Sulfanyl Acid Compound (2^(iv))

Compound (2f) is mixed with diethylamine and cooled in an ice bath. Anaqueous formaldehyde solution (37%) is then added, and the mixturestirred at 0° C. for approximately 2 hours, warmed to room temperatureand stirred overnight. The mixture is then extracted with ether, washed,dried, and evaporated to dryness, to provide compound (2g). Compound(2g) is then dissolved in 1,4-dioxane, and a 1M NaOH solution is added.The mixture is stirred at room temperature until the reaction iscomplete (approximately 2 days). The organic solvent is removed invacuo, and the aqueous residue is rinsed with ethyl acetate andacidified to approximately pH 1 with concentrated HCl. The product isextracted with ethyl acetate, dried, and evaporated to dryness to yieldcompound (2h). Compound (2h) is combined with thiolacetic acid (10 mL),and the mixture is stirred at 80° C. until the reaction is complete(approximately 2 hours), then concentrated to dryness to yield compound(2^(iv)), which is dissolved in toluene and concentrated to remove anytrace of thiolacetic acid. Examples of compound (2f) include2-benzylmalonic acid monoethyl ester (R⁶=benzyl) and 2-isobutylmalonicacid monoethyl ester (R⁶=isobutyl).

Preparation of Chiral Sulfanyl Acid Compound (2^(v))

Compound (2i), (S)-4-benzyl-2-oxazolidinone, is commercially available.Compound (2j) is also typically commercially available or can be readilysynthesized. For example, R⁶—CH₂—COOH (e.g., isocaproic acid or3-phenylpropionic acid) is dissolved in methylene chloride and thionylchloride is added. The mixture is stirred at room temperature until thereaction is complete (e.g., overnight), and then concentrated to provide(2j). Examples of compound (2j) include 4-methylpentanoyl chloride and3-phenylpropionyl chloride.

Compound (2i) is dissolved in a suitable solvent and cooled (−78° C.)under nitrogen. n-Butyllithium in hexanes is added dropwise and stirred,followed by the addition of (2j) dropwise. The mixture is stirred at−78° C., then warmed to 0° C. Saturated NaHCO₃ is added and the mixturewarmed to room temperature. The mixture is extracted, washed, dried,filtered, and concentrated to afford (2k). Compound (2k) is dissolved inDCM and stirred at 0° C. under nitrogen. 1M Titanium tetrachloride isadded, followed by 1,3,5-trioxane, all in appropriate solvents. A secondequivalent of 1M titanium tetrachloride is added and the mixture stirredat 0° C. until the reaction is complete. The mixture is then quenchedwith saturated ammonium chloride. Appropriate solvents are added, theaqueous phase is extracted, and the organic layers are combined, dried,filtered, and concentrated to provide (2l), which can then be purifiedby silica gel chromatography or used in the next step without furtherpurification. Compound (2l) is dissolved in a solvent, to which is added9 M hydrogen peroxide in water, followed by the dropwise addition of 1.5M lithium hydroxide monohydrate in water. The mixture is warmed to roomtemperature and stirred. Optionally, potassium hydroxide may be addedand the mixture heated at 60° C. then cooled at room temperature. Tothis is added an aqueous solution of sodium sulfite followed by waterand chloroform. The aqueous layer is extracted, acidified and extractedagain. The organic layer is washed, dried, filtered, and rotovaped toprovide (2m). Triphenylphosphine is dissolved in an appropriate solventand cooled at 0° C. (ice bath). Diisopropyl azodicarboxylate is addeddropwise and the mixture stirred. Compound (2m) and thioacetic acid,dissolved in an appropriate solvent, are added dropwise to the mixture.After the addition, the mixture is removed from the ice bath and stirredat room temperature until the reaction is complete (approximately 3.5hours), concentrated, and then partitioned. The organic layer isextracted and the combined aqueous extracts washed, acidified andextracted. The organic layer is washed again, dried, filtered, androtovaped to provide compound (2^(v)). Examples of compound (2^(v))include (S)-2-acetylsulfanylmethyl-4-methylpentanoic acid.

Peptide Coupling Reaction and Optional Deprotection-Non-Amide Containing“X” Group

Scheme II can be used to prepare compound of the invention where X is—SO₂NHC(O)—. Such compounds may be formed by a coupling reaction underconventional amide bond-forming conditions, followed by a deprotectionstep if needed.

Compounds (1′) and (2′) can be prepared as described above for compounds(1) and (2).

If desired, pharmaceutically acceptable salts of the compounds offormula I can be prepared by contacting the free acid or base form of acompound of formula I with a pharmaceutically acceptable base or acid.

Certain intermediates described herein are believed to be novel andaccordingly, such compounds are provided as further aspects of theinvention including, for example, the compounds of formula II, and saltsthereof:

Where Q, W, Y, Z, r, and Ar—X, R⁶ and R⁷ are as defined for formula I;and R⁵* is selected from —C₀₋₃alkylene-S—P³, —C₀₋₃alkylene-C(O)NH(O—P⁵),—C₀₋₃alkylene-N(O—P⁵)—C(O)R^(5d), —C₀₋₁alkylene-NHC(O)CH₂S—P³,—NH—C₀₋₁alkylene-P(O)(O—P⁷)₂, —C₀₋₃alkylene-P(O)(O—P⁷)—R^(5e),—C₀₋₂alkylene-CHR^(5f)—C(O)O—P² and—C₀₋₃alkylene-C(O)NR^(5g)—CHR^(5h)—C(O)O—P²; and R^(5d-h) are as definedfor formula I; where P² is a carboxy-protecting group, P³ is athiol-protecting group, P⁵ is a hydroxyl-protecting group, and P⁷ is aphosphate-protecting group. Thus, another method of preparing compoundsof the invention involves deprotecting a compound of formula II.

Further details regarding specific reaction conditions and otherprocedures for preparing representative compounds of the invention orintermediates thereof are described in the Examples set forth below.

Utility

Compounds of the invention possess angiotensin II type 1 (AT₁) receptorantagonist activity. In one embodiment, compounds of the invention areselective for inhibition of the AT₁ receptor over the AT₂ receptor.Compounds of the invention also possess neprilysin (NEP) inhibitionactivity, that is, the compounds are able to inhibit enzyme-substrateactivity. In another embodiment, the compounds do not exhibitsignificant inhibitory activity of the angiotensin-converting enzyme.Compounds of formula I may be active drugs as well as prodrugs. Thus,when discussing the activity of compounds of the invention, it isunderstood that any such prodrugs have the expected AT₁ and NEP activityonce metabolized.

One measure of a compound's affinity for the AT₁ receptor is theinhibitory constant (K_(i)) for binding to the AT₁ receptor. The pK_(i)value is the negative logarithm to base 10 of the K_(i). One measure ofthe ability of a compound to inhibit NEP activity is the inhibitoryconcentration (IC₅₀), which is the concentration of compound thatresults in half-maximal inhibition of substrate conversion by the NEPenzyme. The pIC₅₀ value is the negative logarithm to base 10 of theIC₅₀. Compounds of the invention that have both AT₁receptor-antagonizing activity and NEP enzyme-inhibiting activity are ofparticular interest, including those that exhibit a pK_(i) at the AT₁receptor greater than or equal to about 5.0, and having a pIC₅₀ for NEPgreater than or equal to about 5.0.

In one embodiment, compounds of interest have a pK_(i) at the AT₁receptor ≧about 6.0, a pK_(i) at the AT₁ receptor ≧about 7.0, or apK_(i) at the AT₁ receptor ≧about 8.0. Compounds of interest alsoinclude those having a pIC₅₀ for NEP ≧about 6.0 or a pIC₅₀ for NEP≧about 7.0. In another embodiment, compounds of interest have a pK_(i)at the AT₁ receptor within the range of about 8.0-10.0 and a pIC₅₀ forNEP within the range of about 7.0-10.0.

In another embodiment, compounds of particular interest have a pK_(i)for binding to an AT₁ receptor greater than or equal to about 7.5 and aNEP enzyme pIC₅₀ greater than or equal to about 7.0. In anotherembodiment, compounds of interest have a pK_(i) greater than or equal toabout 8.0 and a pIC₅₀ greater than or equal to about 8.0.

It is noted that in some cases, compounds of the invention, while stillhaving dual activity, may possess either weak AT₁ receptor antagonistactivity or weak NEP inhibition activity. In such cases, those of skillin the art will recognize that these compounds still have utility asprimarily either a NEP inhibitor or a AT₁ receptor antagonist,respectively, or have utility as research tools.

Exemplary assays to determine properties of compounds of the invention,such as the AT₁ receptor binding and/or NEP inhibiting activity, aredescribed in the Examples and include by way of illustration and notlimitation, assays that measure AT₁ and AT₂ binding (described in Assay1), and NEP inhibition (described in Assay 2). Useful secondary assaysinclude assays to measure ACE inhibition (also described in Assay 2) andaminopeptidase P (APP) inhibition (described in Sulpizio et al. (2005)JPET 315:1306-1313). A pharmacodynamic assay to assess the in vivoinhibitory potencies for ACE, AT₁, and NEP in anesthetized rats isdescribed in Assay 3 (see also Seymour et al. (1985) Hypertension7(Suppl 1):1-35-1-42 and Wigle et al. (1992) Can. J. Physiol. Pharmacol.70:1525-1528), where AT₁ inhibition is measured as the percentinhibition of the angiotensin II pressor response, ACE inhibition ismeasured as the percent inhibition of the angiotensin I pressorresponse, and NEP inhibition is measured as increased urinary cyclicguanosine 3′,5′-monophosphate (cGMP) output. Useful in vivo assaysinclude the conscious spontaneously hypertensive rat (SHR) model, whichis a renin dependent hypertension model that is useful for measuring AT₁receptor blocking (described in Assay 4; see also Intengan et al. (1999)Circulation 100(22):2267-2275 and Badyal et al. (2003) Indian Journal ofPharmacology 35:349-362), and the conscious desoxycorticosteroneacetate-salt (DOCA-salt) rat model, which is a volume dependenthypertension model that is useful for measuring NEP activity (describedin Assay 5; see also Trapani et al. (1989) J. Cardiovasc. Pharmacol.14:419-424, Intengan et al. (1999) Hypertension 34(4):907-913, andBadyal et al. (2003) supra). Both the SHR and DOCA-salt models areuseful for evaluating the ability of a test compound to reduce bloodpressure. The DOCA-salt model is also useful to measure a testcompound's ability to prevent or delay a rise in blood pressure.Compounds of the invention are expected to antagonize the AT₁ receptorand/or inhibit the NEP enzyme in any of the assays listed above, orassays of a similar nature. Thus, the aforementioned assays are usefulin determining the therapeutic utility of compounds of the invention,for example, their utility as antihypertensive agents. Other propertiesand utilities of compounds of the invention can be demonstrated usingother in vitro and in vivo assays well known to those skilled in theart.

Compounds of the invention are expected to be useful for the treatmentand/or prevention of medical conditions responsive to AT₁ receptorantagonism and/or NEP inhibition. Thus it is expected that patientssuffering from a disease or disorder that is treated by antagonizing theAT₁ receptor and/or by inhibiting the NEP enzyme can be treated byadministering a therapeutically effective amount of a compound of theinvention. For example, by antagonizing the AT₁ receptor and thusinterfering with the action of angiotensin II on its receptors, thesecompounds are expected to find utility in preventing the increase inblood pressure produced by angiotensin II, a potent vasopressor. Inaddition, by inhibiting NEP, these compounds are also expected topotentiate the biological effects of endogenous peptides that aremetabolized by NEP, such as the natriuretic peptides, bombesin,bradykinins, calcitonin, endothelins, enkephalins, neurotensin,substance P and vasoactive intestinal peptide. For example, bypotentiating the effects of the natriuretic peptides, compounds of theinvention are expected to be useful to treat glaucoma. These compoundsare also expected to have other physiological actions, for example, onthe renal, central nervous, reproductive and gastrointestinal systems.

Compounds of the invention are expected to find utility in treatingand/or preventing medical conditions such as cardiovascular and renaldiseases. Cardiovascular diseases of particular interest include heartfailure such as congestive heart failure, acute heart failure, chronicheart failure, and acute and chronic decompensated heart failure. Renaldiseases of particular interest include diabetic nephropathy and chronickidney disease. One embodiment of the invention relates to a method fortreating hypertension, comprising administering to a patient atherapeutically effective amount of a compound of the invention.Typically, the therapeutically effective amount is the amount that issufficient to lower the patient's blood pressure. In one embodiment, thecompound is administered as an oral dosage form.

Another embodiment of the invention relates to a method for treatingheart failure, comprising administering to a patient a therapeuticallyeffective amount of a compound of the invention. Typically, thetherapeutically effective amount is the amount that is sufficient tolower blood pressure and/or improve renal functions. In one embodiment,the compound is administered as an intravenous dosage form. When used totreat heart failure, the compound may be administered in combinationwith other therapeutic agents such as diuretics, natriuretic peptides,and adenosine receptors antagonist.

Compounds of the invention are also expected to be useful inpreventative therapy, for example in preventing the progression ofcardiac insufficiency after myocardial infarction, preventing arterialrestenosis after angioplasty, preventing thickening of blood vesselwalls after vascular operations, preventing atherosclerosis, andpreventing diabetic angiopathy.

In addition, as NEP inhibitors, compounds of the invention are expectedto inhibit enkephalinase, which will inhibit the degradation ofendogenous enkephalins. Thus, such compounds may also find utility asanalgesics. Due to their NEP inhibition properties, compounds of theinvention are also expected to be useful as antitussive agents andantidiarrheal agents (e.g., for the treatment of watery diarrhea), aswell as find utility in the treatment of menstrual disorders, pretermlabor, pre-eclampsia, endometriosis, reproductive disorders (e.g., maleand female infertility, polycystic ovarian syndrome, implantationfailure), and male and female sexual dysfunction, including maleerectile dysfunction and female sexual arousal disorder. Morespecifically, the compounds of the invention are expected to be usefulin treating female sexual dysfunction, which is often defined as afemale patient's difficulty or inability to find satisfaction in sexualexpression. This covers a variety of diverse female sexual disordersincluding, by way of illustration and not limitation, hypoactive sexualdesire disorder, sexual arousal disorder, orgasmic disorder and sexualpain disorder. When used to treat such disorders, especially femalesexual dysfunction, compounds of the invention may be combined with oneor more of the following secondary agents: PDE5 inhibitors, dopamineagonists, estrogen receptor agonists and/or antagonists, androgens, andestrogens.

The amount of the compound of the invention administered per dose or thetotal amount administered per day may be predetermined or it may bedetermined on an individual patient basis by taking into considerationnumerous factors, including the nature and severity of the patient'scondition, the condition being treated, the age, weight, and generalhealth of the patient, the tolerance of the patient to the compound, theroute of administration, pharmacological considerations such as theactivity, efficacy, pharmacokinetics and toxicology profiles of thecompound and any secondary agents being administered, and the like.Treatment of a patient suffering from a disease or medical condition(such as hypertension) can begin with a predetermined dosage or a dosagedetermined by the treating physician, and then continue for the periodof time necessary to prevent, ameliorate, suppress, or alleviate thesymptoms of the disease or medical condition. Patients undergoing suchtreatment will typically be monitored on a routine basis to determinethe effectiveness of therapy. For example, in treating hypertension,blood pressure measurements may be used to determine the effectivenessof treatment. Similar indicators for the other diseases and conditionsdescribed herein, are well known and are readily available to thetreating physician. Continuous monitoring by the physician will insurethat the optimal amount of the compound of the invention will beadministered at any given time, as well as facilitating thedetermination of the duration of treatment. This is of particular valuewhen secondary agents are also being administered, as their selection,dosage, and duration of therapy may also require adjustment. In thisway, the treatment regimen and dosing schedule can be adjusted over thecourse of therapy so that the lowest amount of compound that exhibitsthe desired effectiveness is administered and, further, thatadministration is continued only so long as is necessary to successfullytreat the disease or medical condition.

Since compounds of the invention possess AT₁ receptor antagonistactivity and/or NEP enzyme inhibition activity, these compounds are alsouseful as research tools for investigating or studying biologicalsystems or samples having AT₁ receptors or a NEP enzyme, for example tostudy diseases where the AT₁ receptor or NEP enzyme plays a role. Anysuitable biological system or sample having AT₁ receptors and/or a NEPenzyme may be employed in such studies which may be conducted either invitro or in vivo. Representative biological systems or samples suitablefor such studies include, but are not limited to, cells, cellularextracts, plasma membranes, tissue samples, isolated organs, mammals(such as mice, rats, guinea pigs, rabbits, dogs, pigs, humans, and soforth), and the like, with mammals being of particular interest. In oneparticular embodiment of the invention an AT₁ receptor in a mammal isantagonized by administering an AT₁-antagonizing amount of a compound ofthe invention. In another particular embodiment, NEP enzyme activity ina mammal is inhibited by administering a NEP-inhibiting amount of acompound of the invention. Compounds of the invention can also be usedas research tools by conducting biological assays using these compounds.

When used as a research tool, a biological system or sample comprisingan AT₁ receptor and/or a NEP enzyme is typically contacted with an AT₁receptor-antagonizing or NEP enzyme-inhibiting amount of a compound ofthe invention. After the biological system or sample is exposed to thecompound, the effects of antagonizing the AT₁ receptor and/or inhibitingthe NEP enzyme are determined using conventional procedures andequipment, such as by measuring receptor binding in a binding assay ormeasuring ligand-mediated changes in a functional assay. Exposureencompasses contacting cells or tissue with the compound, administeringthe compound to a mammal, for example by i.p., i.v. or s.c.administration, and so forth. The determining step can involve measuringa response (a quantitative analysis) or can involve making anobservation (a qualitative analysis). Measuring a response involves, forexample, determining the effects of the compound on the biologicalsystem or sample using conventional procedures and equipment, such asradioligand binding assays or measuring ligand-mediated changes infunctional assays. The assay results can be used to determine theactivity level as well as the amount of compound necessary to achievethe desired result, such as an AT₁ receptor-antagonizing and/or a NEPenzyme-inhibiting amount. Typically, the determining step will involvedetermining the AT₁ receptor ligand-mediated effects and/or determiningthe effects of inhibiting the NEP enzyme.

Additionally, compounds of the invention can be used as research toolsfor evaluating other chemical compounds, and thus are also useful inscreening assays to discover, for example, new compounds having AT₁receptor-antagonizing activity and/or NEP-inhibiting activity. In thismanner, a compound of the invention is used as a standard in an assay toallow comparison of the results obtained with a test compound and withcompounds of the invention to identify those test compounds that haveabout equal or superior activity, if any. For example, K_(i) data (asdetermined, for example, by a binding assay) for a test compound or agroup of test compounds is compared to the K_(i) data for a compound ofthe invention to identify those test compounds that have the desiredproperties, for example, test compounds having a K_(i) value about equalor superior to a compound of the invention, if any. This aspect of theinvention includes, as separate embodiments, both the generation ofcomparison data (using the appropriate assays) and the analysis of testdata to identify test compounds of interest. Thus, a test compound canbe evaluated in a biological assay, by a method comprising the steps of:(a) conducting a biological assay with a test compound to provide afirst assay value; (b) conducting the biological assay with a compoundof the invention to provide a second assay value; wherein step (a) isconducted either before, after or concurrently with step (b); and (c)comparing the first assay value from step (a) with the second assayvalue from step (b). Exemplary biological assays include AT₁ receptorbinding assays and NEP enzyme inhibition assays.

Pharmaceutical Compositions and Formulations

Compounds of the invention are typically administered to a patient inthe form of a pharmaceutical composition or formulation. Suchpharmaceutical compositions may be administered to the patient by anyacceptable route of administration including, but not limited to, oral,rectal, vaginal, nasal, inhaled, topical (including transdermal),ocular, and parenteral modes of administration. Further, the compoundsof the invention may be administered, for example orally, in multipledoses per day (e.g., two, three, or four times daily), in a single dailydose or a single weekly dose. It will be understood that any form of thecompounds of the invention, (e.g., free base, free acid,pharmaceutically acceptable salt, solvate, etc.) that is suitable forthe particular mode of administration can be used in the pharmaceuticalcompositions discussed herein.

Accordingly, in one embodiment, the invention relates to apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of the invention. The compositions may containother therapeutic and/or formulating agents if desired. When discussingcompositions, the “compound of the invention” may also be referred toherein as the “active agent,” to distinguish it from other components ofthe formulation, such as the carrier. Thus, it is understood that theterm “active agent” includes compounds of formula I as well aspharmaceutically acceptable salts, solvates and prodrugs of thatcompound.

The pharmaceutical compositions of the invention typically contain atherapeutically effective amount of a compound of the invention. Thoseskilled in the art will recognize, however, that a pharmaceuticalcomposition may contain more than a therapeutically effective amountsuch as in bulk compositions, or less than a therapeutically effectiveamount such as in individual unit doses designed for multipleadministration to achieve a therapeutically effective amount. Typically,the composition will contain from about 0.01-95 wt % of active agent,including, from about 0.01-30 wt %, such as from about 0.01-10 wt %,with the actual amount depending upon the formulation itself, the routeof administration, the frequency of dosing, and so forth. In oneembodiment, a composition suitable for an oral dosage form, for example,may contain about 5-70 wt %, or from about 10-60 wt % of active agent.

Any conventional carrier or excipient may be used in the pharmaceuticalcompositions of the invention. The choice of a particular carrier orexcipient, or combinations of carriers or excipients, will depend on themode of administration being used to treat a particular patient or typeof medical condition or disease state. In this regard, the preparationof a suitable composition for a particular mode of administration iswell within the scope of those skilled in the pharmaceutical arts.Additionally, carriers or excipients used in such compositions arecommercially available. By way of further illustration, conventionalformulation techniques are described in Remington: The Science andPractice of Pharmacy, 20^(th) Edition, Lippincott Williams & White,Baltimore, Md. (2000); and H. C. Ansel et al., Pharmaceutical DosageForms and Drug Delivery Systems, 7^(th) Edition, Lippincott Williams &White, Baltimore, Md. (1999).

Representative examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, the following:sugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose, such as microcrystalline cellulose,and its derivatives, such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients, such as cocoa butter and suppository waxes; oils, suchas peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil and soybean oil; glycols, such as propylene glycol; polyols,such as glycerin, sorbitol, mannitol and polyethylene glycol; esters,such as ethyl oleate and ethyl laurate; agar; buffering agents, such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol; phosphatebuffer solutions; compressed propellant gases, such aschlorofluorocarbons and hydrofluorocarbons; and other non-toxiccompatible substances employed in pharmaceutical compositions.

Pharmaceutical compositions are typically prepared by thoroughly andintimately mixing or blending the active agent with a pharmaceuticallyacceptable carrier and one or more optional ingredients. The resultinguniformly blended mixture may then be shaped or loaded into tablets,capsules, pills, canisters, cartridges, dispensers and the like usingconventional procedures and equipment.

In formulations where the compound of the invention contains a thiolgroup, additional consideration may be given to minimize or eliminateoxidation of the thiol to form a disulfide. In solid formulations, thismay be accomplished by reducing the drying time, decreasing the moisturecontent of the formulation, and including materials such as ascorbicacid, sodium ascorbate, sodium sulfite and sodium bisulfite, as well asmaterials such as a mixture of lactose and microcrystalline cellulose.In liquid formulations, stability of the thiol may be improved by theaddition of amino acids, antioxidants, or a combination of disodiumedetate and ascorbic acid.

In one embodiment, the pharmaceutical compositions are suitable for oraladministration. Suitable compositions for oral administration may be inthe form of capsules, tablets, pills, lozenges, cachets, dragees,powders, granules; solutions or suspensions in an aqueous or non-aqueousliquid; oil-in-water or water-in-oil liquid emulsions; elixirs orsyrups; and the like; each containing a predetermined amount of theactive agent.

When intended for oral administration in a solid dosage form (capsules,tablets, pills and the like), the composition will typically comprisethe active agent and one or more pharmaceutically acceptable carriers,such as sodium citrate or dicalcium phosphate. Solid dosage forms mayalso comprise: fillers or extenders, such as starches, microcrystallinecellulose, lactose, sucrose, glucose, mannitol, and/or silicic acid;binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; humectants, such as glycerol;disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and/or sodiumcarbonate; solution retarding agents, such as paraffin; absorptionaccelerators, such as quaternary ammonium compounds; wetting agents,such as cetyl alcohol and/or glycerol monostearate; absorbents, such askaolin and/or bentonite clay; lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, and/or mixtures thereof; coloring agents; and buffering agents.

Release agents, wetting agents, coating agents, sweetening, flavoringand perfuming agents, preservatives and antioxidants may also be presentin the pharmaceutical compositions. Exemplary coating agents fortablets, capsules, pills and like, include those used for entericcoatings, such as cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate, methacrylicacid-methacrylic acid ester copolymers, cellulose acetate trimellitate,carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetatesuccinate, and the like. Examples of pharmaceutically acceptableantioxidants include: water-soluble antioxidants, such as ascorbic acid,cysteine hydrochloride, sodium bisulfate, sodium metabisulfate sodiumsulfite and the like; oil-soluble antioxidants, such as ascorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin,propyl gallate, alpha-tocopherol, and the like; and metal-chelatingagents, such as citric acid, ethylenediamine tetraacetic acid, sorbitol,tartaric acid, phosphoric acid, and the like.

Compositions may also be formulated to provide slow or controlledrelease of the active agent using, by way of example, hydroxypropylmethyl cellulose in varying proportions or other polymer matrices,liposomes and/or microspheres. In addition, the pharmaceuticalcompositions of the invention may contain opacifying agents and may beformulated so that they release the active agent only, orpreferentially, in a certain portion of the gastrointestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes. The activeagent can also be in micro-encapsulated form, optionally with one ormore of the above-described excipients.

Suitable liquid dosage forms for oral administration include, by way ofillustration, pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. Liquid dosage formstypically comprise the active agent and an inert diluent, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof. Suspensions maycontain suspending agents such as, for example, ethoxylated isostearylalcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

When intended for oral administration, the pharmaceutical compositionsof the invention may be packaged in a unit dosage form. The term “unitdosage form” refers to a physically discrete unit suitable for dosing apatient such that each unit contains a predetermined quantity of theactive agent calculated to produce the desired therapeutic effect eitheralone or in combination with one or more additional units. For example,such unit dosage forms may be capsules, tablets, pills, and the like.

In another embodiment, the compositions of the invention are suitablefor inhaled administration, and will typically be in the form of anaerosol or a powder. Such compositions are generally administered usingwell known delivery devices, such as a nebulizer, dry powder, ormetered-dose inhaler. Nebulizer devices produce a stream of highvelocity air that causes the composition to spray as a mist that iscarried into a patient's respiratory tract. An exemplary nebulizerformulation comprises the active agent dissolved in a carrier to form asolution, or micronized and combined with a carrier to form a suspensionof micronized particles of respirable size. Dry powder inhalersadminister the active agent as a free-flowing powder that is dispersedin a patient's air-stream during inspiration. An exemplary dry powderformulation comprises the active agent dry-blended with an excipientsuch as lactose, starch, mannitol, dextrose, polylactic acid,polylactide-co-glycolide, and combinations thereof. Metered-doseinhalers discharge a measured amount of the active agent usingcompressed propellant gas. An exemplary metered-dose formulationcomprises a solution or suspension of the active agent in a liquefiedpropellant, such as a chlorofluorocarbon or hydrofluoroalkane. Optionalcomponents of such formulations include co-solvents, such as ethanol orpentane, and surfactants, such as sorbitan trioleate, oleic acid,lecithin, glycerin, and sodium lauryl sulfate. Such compositions aretypically prepared by adding chilled or pressurized hydrofluoroalkane toa suitable container containing the active agent, ethanol (if present)and the surfactant (if present). To prepare a suspension, the activeagent is micronized and then combined with the propellant.Alternatively, a suspension formulation can be prepared by spray dryinga coating of surfactant on micronized particles of the active agent. Theformulation is then loaded into an aerosol canister, which forms aportion of the inhaler.

Compounds of the invention can also be administered parenterally (e.g.,by subcutaneous, intravenous, intramuscular, or intraperitonealinjection). For such administration, the active agent is provided in asterile solution, suspension, or emulsion. Exemplary solvents forpreparing such formulations include water, saline, low molecular weightalcohols such as propylene glycol, polyethylene glycol, oils, gelatin,fatty acid esters such as ethyl oleate, and the like. Parenteralformulations may also contain one or more anti-oxidants, solubilizers,stabilizers, preservatives, wetting agents, emulsifiers, and dispersingagents. Surfactants, additional stabilizing agents or pH-adjustingagents (acids, bases or buffers) and anti-oxidants are particularlyuseful to provide stability to the formulation, for example, to minimizeor avoid hydrolysis of ester and amide linkages, or dimerization ofthiols that may be present in the compound. These formulations may berendered sterile by use of a sterile injectable medium, a sterilizingagent, filtration, irradiation, or heat. In one particular embodiment,the parenteral formulation comprises an aqueous cyclodextrin solution asthe pharmaceutically acceptable carrier. Suitable cyclodextrins includecyclic molecules containing six or more α-D-glucopyranose units linkedat the 1,4 positions by a linkages as in amylase, β-cyclodextrin orcycloheptaamylose. Exemplary cyclodextrins include cyclodextrinderivatives such as hydroxypropyl and sulfobutyl ether cyclodextrinssuch as hydroxypropyl-β-cyclodextrin and sulfobutyl etherβ-cyclodextrin. Exemplary buffers for such formulations includecarboxylic acid-based buffers such as citrate, lactate and maleatebuffer solutions.

Compounds of the invention can also be administered transdermally usingknown transdermal delivery systems and excipients. For example, thecompound can be admixed with permeation enhancers, such as propyleneglycol, polyethylene glycol monolaurate, azacycloalkan-2-ones and thelike, and incorporated into a patch or similar delivery system.Additional excipients including gelling agents, emulsifiers and buffers,may be used in such transdermal compositions if desired.

If desired, the compounds of the invention may be administered incombination with one or more other therapeutic agents. Thus, in oneembodiment, pharmaceutical compositions of the invention contain otherdrugs that are co-administered with the compound of the invention. Forexample, the composition may further comprise one or more drugs, alsoreferred to as “secondary agents(s)”, selected from the group ofdiuretics, β₁ adrenergic receptor blockers, calcium channel blockers,angiotensin-converting enzyme inhibitors, AT₁ receptor antagonists,neprilysin inhibitors, non-steroidal anti-inflammatory agents,prostaglandins, anti-lipid agents, anti-diabetic agents, anti-thromboticagents, renin inhibitors, endothelin receptor antagonists, endothelinconverting enzyme inhibitors, aldosterone antagonists,angiotensin-converting enzyme/neprilysin inhibitors, and combinationsthereof. Such therapeutic agents are well known in the art, and specificexamples are described herein. By combining a compound of the inventionwith a secondary agent, triple therapy can be achieved; AT₁ receptorantagonist activity, NEP inhibition activity and activity associatedwith the secondary agent (e.g., β₁ adrenergic receptor blocker) can beachieved using only two active components. Since compositions containingtwo active components are typically easier to formulate thancompositions containing three active components, such two-componentcompositions provide a significant advantage over compositionscontaining three active components. Accordingly, in yet another aspectof the invention, a pharmaceutical composition comprises a compound ofthe invention, a second active agent, and a pharmaceutically acceptablecarrier. Third, fourth, etc. active agents may also be included in thecomposition. In combination therapy, the amount of the compound of theinvention that is administered, as well as the amount of secondaryagents, may be less than the amount typically administered inmonotherapy.

Compounds of the invention may be either physically mixed with thesecond active agent to form a composition containing both agents; oreach agent may be present in separate and distinct compositions whichare administered to the patient simultaneously or at separate times. Forexample, compounds of the invention can be combined with a second activeagent using conventional procedures and equipment to form a combinationof active agents comprising a compound of the invention and a secondactive agent. Additionally, the active agents may be combined with apharmaceutically acceptable carrier to form a pharmaceutical compositioncomprising a compound of the invention, a second active agent and apharmaceutically acceptable carrier. In this embodiment, the componentsof the composition are typically mixed or blended to create a physicalmixture. The physical mixture is then administered in a therapeuticallyeffective amount using any of the routes described herein.

Alternatively, the active agents may remain separate and distinct beforeadministration to the patient. In this embodiment, the agents are notphysically mixed together before administration but are administeredsimultaneously or at separate times as separate compositions. Suchcompositions can be packaged separately or may be packaged together in akit. When administered at separate times, the secondary agent willtypically be administered less than 24 hours after administration of acompound of the invention, ranging anywhere from concurrent withadministration of a compound of the invention to about 24 hourspost-dose. This is also referred to as sequential administration. Thus,compounds of the invention can be orally administered simultaneously orsequentially with another active agent using two tablets, with onetablet for each active agent, where sequential may mean beingadministered immediately after administration of the compound of theinvention or at some predetermined time later (e.g., one hour later orthree hours later). Alternatively, the combination may be administeredby different routes of administration, for example, one orally and theother by inhalation.

In one embodiment, the kit comprises a first dosage form comprising acompound of the invention and at least one additional dosage formcomprising one or more of the secondary agents set forth herein, inquantities sufficient to carry out the methods of the invention. Thefirst dosage form and the second (or third, etc.) dosage form togethercomprise a therapeutically effective amount of active agents for thetreatment or prevention of a disease or medical condition in a patient.

Secondary agent(s), when included, are present in a therapeuticallyeffective amount such that they produce a therapeutically beneficialeffect when co-administered with a compound of the invention. Thesecondary agent can be in the form of a pharmaceutically acceptablesalt, solvate, optically pure stereoisomer, and so forth. The secondaryagent may also be in the form of a prodrug, for example, a compoundhaving a carboxylic acid group that has been esterified. Thus, secondaryagents listed herein are intended to include all such forms, and arecommercially available or can be prepared using conventional proceduresand reagents.

In one embodiment, a compound of the invention is administered incombination with a diuretic. Representative diuretics include, but arenot limited to: carbonic anhydrase inhibitors such as acetazolamide anddichlorphenamide; loop diuretics, which include sulfonamide derivativessuch as acetazolamide, ambuside, azosernide, bumetanide, butazolamide,chloraminophenamide, clofenamide, clopamide, clorexolone, disulfamide,ethoxolamide, furosemide, mefruside, methazolamide, piretanide,torsemide, tripamide, and xipamide, as well as non-sulfonamide diureticssuch as ethacrynic acid and other phenoxyacetic acid compounds such astienilic acid, indacrinone and quincarbate; osmotic diuretics such asmannitol; potassium-sparing diuretics, which include aldosteroneantagonists such as spironolactone, and Na⁺ channel inhibitors such asamiloride and triamterene; thiazide and thiazide-like diuretics such asalthiazide, bendroflumethiazide, benzylhydrochlorothiazide,benzthiazide, buthiazide, chlorthalidone, chlorothiazide,cyclopenthiazide, cyclothiazide, epithiazide, ethiazide, fenquizone,flumethiazide, hydrochlorothiazide, hydroflumethiazide, indapamide,methylclothiazide, meticrane, metolazone, paraflutizide, polythiazide,quinethazone, teclothiazide, and trichloromethiazide; and combinationsthereof. In a particular embodiment, the diuretic is selected fromamiloride, bumetanide, chlorothiazide, chlorthalidone, dichlorphenamide,ethacrynic acid, furosemide, hydrochlorothiazide, hydroflumethiazide,indapamide, methylclothiazide, metolazone, torsemide, triamterene, andcombinations thereof. The diuretic will be administered in an amountsufficient to provide from about 5-50 mg per day, more typically 6-25 mgper day, with common dosages being 6.25 mg, 12.5 mg or 25 mg per day.

Compounds of the invention may also be administered in combination witha β₁ adrenergic receptor blocker. Representative β₁ adrenergic receptorblockers include, but are not limited to, acebutolol, alprenolol,amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol,bisoprolol, bopindolol, bucindolol, bucumolol, bufetolol, bufuralol,bunitrolol, bupranolol, bubridine, butofilolol, carazolol, carteolol,carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol,esmolol, indenolol, labetolol, levobunolol, mepindolol, metipranolol,metoprolol such as metoprolol succinate or metoprolol tartrate,moprolol, nadolol, nadoxolol, nebivalol, nipradilol, oxprenolol,penbutolol, perbutolol, pindolol, practolol, pronethalol, propranolol,sotalol, sufinalol, talindol, tertatolol, tilisolol, timolol,toliprolol, xibenolol, and combinations thereof. In one particularembodiment, the β₁ adrenergic receptor blocker is selected fromatenolol, bisoprolol, metoprolol, propranolol, sotalol, and combinationsthereof.

In one embodiment, a compound of the invention is administered incombination with a calcium channel blocker. Representative calciumchannel blockers include, but are not limited to, amlodipine, anipamil,aranipine, barnidipine, bencyclane, benidipine, bepridil, clentiazem,cilnidipine, cinnarizine, diltiazem, efonidipine, elgodipine, etafenone,felodipine, fendiline, flunarizine, gallopamil, isradipine, lacidipine,lercanidipine, lidoflazine, lomerizine, manidipine, mibefradil,nicardipine, nifedipine, niguldipine, niludipine, nilvadipine,nimodipine, nisoldipine, nitrendipine, nivaldipine, perhexyline,prenylamine, ryosidine, semotiadil, terodiline, tiapamil, verapamil, andcombinations thereof. In one particular embodiment, the calcium channelblocker is selected from amlodipine, bepridil, diltiazem, felodipine,isradipine, lacidipine, nicardipine, nifedipine, niguldipine,niludipine, nimodipine, nisoldipine, ryosidine, verapamil, andcombinations thereof.

Compounds of the invention can also be administered in combination withan angiotensin-converting enzyme (ACE) inhibitor. Representative ACEinhibitors include, but are not limited to, accupril, alacepril,benazepril, benazeprilat, captopril, ceranapril, cilazapril, delapril,enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril,moexipril, monopril, moveltopril, pentopril, perindopril, quinapril,quinaprilat, ramipril, ramiprilat, saralasin acetate, spirapril,temocapril, trandolapril, zofenopril, and combinations thereof. In aparticular embodiment, the ACE inhibitor is selected from benazepril,enalapril, lisinopril, ramipril, and combinations thereof.

In one embodiment, a compound of the invention is administered incombination with an AT₁ receptor antagonist, also known as anangiotensin II type 1 receptor blocker (ARB). Representative ARBsinclude, but are not limited to, abitesartan, benzyllosartan,candesartan, candesartan cilexetil, elisartan, embusartan,enoltasosartan, eprosartan, fonsartan, forasartan, glycyllosartan,irbesartan, isoteoline, losartan, medoximil, milfasartan, olmesartan,opomisartan, pratosartan, ripisartan, saprisartan, saralasin, sarmesin,tasosartan, telmisartan, valsartan, zolasartan, and combinationsthereof. In a particular embodiment, the ARB is selected fromcandesartan, eprosartan, irbesartan, losartan, olmesartan, saprisartan,tasosartan, telmisartan, valsartan, and combinations thereof. Exemplarysalts include eprosartan mesylate, losartan potassium salt, andolmesartan medoxomil. Typically, the ARB will be administered in anamount sufficient to provide from about 4-600 mg per dose, withexemplary daily dosages ranging from 20-320 mg per day.

In another embodiment, a compound of the invention is administered incombination with a neprilysin (NEP) inhibitor. Representative NEPinhibitors include, but are not limited to: candoxatril; candoxatrilat;dexecadotril ((+)-N-[2(R)-(acetylthiomethyl)-3-phenylpropionyl]glycinebenzyl ester); CGS-24128(3-[3-(biphenyl-4-yl)-2-(phosphonomethylamino)propionamido]propionicacid); CGS-24592QS)-3-[3-(biphenyl-4-yl)-2-(phosphonomethylamino)propionamido]propionicacid); CGS-25155(N-[9(R)-(acetylthiomethyl)-10-oxo-1-azacyclodecan-2(S)-ylcarbonyl]-4(R)-hydroxy-L-prolinebenzyl ester); 3-(1-carbamoylcyclohexyl)propionic acid derivativesdescribed in WO 2006/027680 to Hepworth et al. (Pfizer Inc.); JMV-390-1(2(R)-benzyl-3-(N-hydroxycarbamoyl)propionyl-L-isoleucyl-L-leucine);ecadotril; phosphoramidon; retrothiorphan; RU-42827(2-(mercaptomethyl)-N-(4-pyridinyl)benzenepropionamide); RU-44004(N-(4-morpholinyl)-3-phenyl-2-(sulfanylmethyl)propionamide); SCH-32615((S)—N—[N-(1-carboxy-2-phenylethyl)-L-phenylalanyl]-β-alanine) and itsprodrug SCH-34826((S)—N—[N-[1-[[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-β-alanine);sialorphin; SCH-42495(N-[2(S)-(acetylsulfanylmethyl)-3-(2-methylphenyl)propionyl]-L-methionineethyl ester); spinorphin; SQ-28132(N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]leucine); SQ-28603(N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-β-alanine); SQ-29072(7-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]heptanoic acid);thiorphan and its prodrug racecadotril; UK-69578(cis-4-[[[1-[2-carboxy-3-(2-methoxyethoxy)propyl]cyclopentyl]carbonyl]amino]cyclohexanecarboxylicacid); UK-447,841(2-{1-[3-(4-chlorophenyl)propylcarbamoyl]-cyclopentylmethyl}-4-methoxybutyricacid); UK-505,749((R)-2-methyl-3-{1-[3-(2-methylbenzothiazol-6-yl)propylcarbamoyl]cyclopentyl}propionicacid); 5-biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methylpentanoicacid and 5-biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methylpentanoicacid ethyl ester (WO 2007/056546); daglutril[(3S,2′R)-3-{1-[2′-(ethoxycarbonyl)-4′-phenylbutyl]-cyclopentan-1-carbonylamino}-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-aceticacid] described in WO 2007/106708 to Khder et al. (Novartis AG); andcombinations thereof. In a particular embodiment, the NEP inhibitor isselected from candoxatril, candoxatrilat, CGS-24128, phosphoramidon,SCH-32615, SCH-34826, SQ-28603, thiorphan, and combinations thereof. TheNEP inhibitor will be administered in an amount sufficient to providefrom about 20-800 mg per day, with typical daily dosages ranging from50-700 mg per day, more commonly 100-600 or 100-300 mg per day.

In yet another embodiment, a compound of the invention is administeredin combination with a non-steroidal anti-inflammatory agent (NSAID).Representative NSAIDs include, but are not limited to, acemetacin,acetyl salicylic acid, alclofenac, alminoprofen, amfenac, amiprilose,amoxiprin, anirolac, apazone, azapropazone, benorilate, benoxaprofen,bezpiperylon, broperamole, bucloxic acid, carprofen, clidanac,diclofenac, diflunisal, diftalone, enolicam, etodolac, etoricoxib,fenbufen, fenclofenac, fenclozic acid, fenoprofen, fentiazac, feprazone,flufenamic acid, flufenisal, fluprofen, flurbiprofen, furofenac,ibufenac, ibuprofen, indomethacin, indoprofen, isoxepac, isoxicam,ketoprofen, ketorolac, lofemizole, lomoxicam, meclofenamate,meclofenamic acid, mefenamic acid, meloxicam, mesalamine, miroprofen,mofebutazone, nabumetone, naproxen, niflumic acid, oxaprozin, oxpinac,oxyphenbutazone, phenylbutazone, piroxicam, pirprofen, pranoprofen,salsalate, sudoxicam, sulfasalazine, sulindac, suprofen, tenoxicam,tiopinac, tiaprofenic acid, tioxaprofen, tolfenamic acid, tolmetin,triflumidate, zidometacin, zomepirac, and combinations thereof. In aparticular embodiment, the NSAID is selected from etodolac,flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meloxicam,naproxen, oxaprozin, piroxicam, and combinations thereof.

In yet another embodiment, a compound of the invention is administeredin combination with an anti-lipid agent. Representative anti-lipidagents include, but are not limited to: statins such as atorvastatin,fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin;cholesteryl ester transfer proteins (CETPs); and combinations thereof.

In yet another embodiment, a compound of the invention is administeredin combination with an anti-diabetic agent. Representative anti-diabeticagents include, injectable drugs as well as orally effective drugs, andcombinations thereof. Examples of injectable drugs include, but are notlimited to, insulin and insulin derivatives. Examples of orallyeffective drugs include, but are not limited to: biguanides such asmetformin; glucagon antagonists; α-glucosidase inhibitors such asacarbose and miglitol; meglitinides such as repaglinide;oxadiazolidinediones; sulfonylureas such as chlorpropamide, glimepiride,glipizide, glyburide and tolazamide; thiazolidinediones such aspioglitazone and rosiglitazone; and combinations thereof.

In one embodiment, a compound of the invention is administered incombination with an anti-thrombotic agent, representative examples ofwhich include, but are not limited to, aspirin, anti-platelet agents,heparin, and combinations thereof. Compounds of the invention may alsobe administered in combination with a renin inhibitor, examples of whichinclude, but are not limited to, aliskiren, enalkiren, remikiren, andcombinations thereof. In another embodiment, a compound of the inventionis administered in combination with an endothelin receptor antagonist,representative examples of which include, but are not limited to,bosentan, darusentan, tezosentan, and combinations thereof. Compounds ofthe invention may also be administered in combination with an endothelinconverting enzyme inhibitor, examples of which include, but are notlimited to, phosphoramidon, CGS 26303, and combinations thereof. In yetanother embodiment, a compound of the invention is administered incombination with an aldosterone antagonist, representative examples ofwhich include, but are not limited to, eplerenone, spironolactone, andcombinations thereof.

Combined therapeutic agents may also be helpful in further combinationtherapy with compounds of the invention. For example, a combination ofthe ACE inhibitor enalapril (in the maleate salt form) and the diuretichydrochlorothiazide, which is sold under the mark Vaseretic®, or acombination of the calcium channel blocker amlodipine (in the besylatesalt form) and the ARB olmesartan (in the medoxomil prodrug form), or acombination of a calcium channel blocker and a statin, all may also beused with the compounds of the invention. Dual-acting agents may also behelpful in combination therapy with compounds of the invention. Forexample, angiotensin-converting enzyme/neprilysin (ACE/NEP) inhibitorssuch as: AVE-0848((4S,7S,12bR)-7-[3-methyl-2(S)-sulfanylbutyramido]-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylicacid); AVE-7688 (ilepatril) and its parent compound; BMS-182657(2-[2-oxo-3(S)-[3-phenyl-2(S)-sulfanylpropionamido]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]aceticacid); CGS-26303([N-[2-(biphenyl-4-yl)-1(S)-(1H-tetrazol-5-yl)ethyl]amino]methylphosphonicacid); CGS-35601(N-[1-[4-methyl-2(S)-sulfanylpentanamido]cyclopentylcarbonyl]-L-tryptophan);fasidotril; fasidotrilate; enalaprilat; ER-32935((3R,6S,9aR)-6-[3(S)-methyl-2(S)-sulfanylpentanamido]-5-oxoperhydrothiazolo[3,2-a]azepine-3-carboxylicacid); gempatrilat; MDL-101264((4S,7S,12bR)-7-[2(S)-(2-morpholinoacetylthio)-3-phenylpropionamido]-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylicacid); MDL-101287([4S-[4α,7α(R*),12bβ]]-7-[2-(carboxymethyl)-3-phenylpropionamido]-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylicacid); omapatrilat; RB-105(N-[2(S)-(mercaptomethyl)-3(R)-phenylbutyl]-L-alanine); sampatrilat;SA-898((2R,4R)—N-[2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)thiazolidin-4-ylcarbonyl]-L-phenylalanine);Sch-50690(N-[1(S)-carboxy-2-[N²-(methanesulfonyl)-L-lysylamino]ethyl]-L-valyl-L-tyrosine);and combinations thereof, may also be included. In one particularembodiment, the ACE/NEP inhibitor is selected from: AVE-7688,enalaprilat, fasidotril, fasidotrilate, omapatrilat, sampatrilat, andcombinations thereof.

Other therapeutic agents such as α₂-adrenergic receptor agonists andvasopressin receptor antagonists may also be helpful in combinationtherapy. Exemplary α₂-adrenergic receptor agonists include clonidine,dexmedetomidine, and guanfacine. Exemplary vasopressin receptorantagonists include tolvaptan.

The following formulations illustrate representative pharmaceuticalcompositions of the invention.

Exemplary Hard Gelatin Capsules for Oral Administration

A compound of the invention (50 g), spray-dried lactose (440 g), andmagnesium stearate (10 g) are thoroughly blended. The resultingcomposition is then loaded into hard gelatin capsules (500 mg ofcomposition per capsule). Alternately, a compound of the invention (20mg) is thoroughly blended with starch (89 mg), microcrystallinecellulose (89 mg), and magnesium stearate (2 mg). The mixture is thenpassed through a No. 45 mesh U.S. sieve and loaded into a hard gelatincapsule having 200 mg of composition per capsule.

Exemplary Gelatin Capsule Formulation for Oral Administration

A compound of the invention (100 mg) is thoroughly blended withpolyoxyethylene sorbitan monooleate (50 mg) and starch powder (250 mg).The mixture is then loaded into a gelatin capsule (300 mg of compositionper capsule). Alternately, a compound of the invention (40 mg) isthoroughly blended with microcrystalline cellulose (Avicel PH 103; 260mg) and magnesium stearate (0.8 mg). The mixture is then loaded into agelatin capsule (Size #1, White, Opaque; 300 mg of composition percapsule).

Exemplary Tablet Formulation for Oral Administration

A compound of the invention (10 mg), starch (45 mg), andmicrocrystalline cellulose (35 mg) are passed through a No. 20 mesh U.S.sieve and mixed thoroughly. The granules so produced are dried at 50-60°C. and passed through a No. 16 mesh U.S. sieve. A solution ofpolyvinylpyrrolidone (4 mg as a 10% solution in sterile water) is mixedwith sodium carboxymethyl starch (4.5 mg), magnesium stearate (0.5 mg),and talc (1 mg), and this mixture is then passed through a No. 16 meshU.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talcare then added to the granules. After mixing, the mixture is compressedon a tablet machine to afford a 100 mg tablet.

Alternately, a compound of the invention (250 mg) is thoroughly blendedwith microcrystalline cellulose (400 mg), silicon dioxide (fumed, 10mg), and stearic acid (5 mg). The mixture is then compressed to formtablets (665 mg of composition per tablet).

Alternately, a compound of the invention (400 mg) is thoroughly blendedwith cornstarch (50 mg), croscarmellose sodium (25 mg), lactose (120mg), and magnesium stearate (5 mg). The mixture is then compressed toform a single-scored tablet having 600 mg of composition per tablet.

Alternately, a compound of the invention (100 mg) is thoroughly blendedwith cornstarch (100 mg) and an aqueous solution of gelatin (20 mg). Themixture is dried and ground to a fine powder. Microcrystalline cellulose(50 mg) and magnesium stearate (5 mg) are the admixed with the gelatinformulation, granulated and the resulting mixture compressed to formtablets (100 mg of the compound of the invention per tablet).

Exemplary Suspension Formulation for Oral Administration

The following ingredients are mixed to form a suspension containing 100mg of the compound of the invention per 10 mL of suspension:

Ingredients Amount Compound of the invention 1.0 g Fumaric acid 0.5 gSodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 gGranulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum ® K(magnesium aluminum silicate) 1.0 g Flavoring 0.035 mL Colorings 0.5 mgDistilled water q.s. to 100 mL

Exemplary Liquid Formulation for Oral Administration

A suitable liquid formulation is one with a carboxylic acid-based buffersuch as citrate, lactate and maleate buffer solutions. For example, acompound of the invention (which may be pre-mixed with DMSO) is blendedwith a 100 mM ammonium citrate buffer and the pH adjusted to pH 5, orwith is blended with a 100 mM citric acid solution and the pH adjustedto pH 2. Such solutions may also include a solubilizing excipient suchas a cyclodextrin, for example the solution may include 10 wt %hydroxypropyl-β-cyclodextrin.

Exemplary Injectable Formulation for Administration by Injection

A compound of the invention (0.2 g) is blended with 0.4 M sodium acetatebuffer solution (2.0 mL). The pH of the resulting solution is adjustedto pH 4 using 0.5 N aqueous hydrochloric acid or 0.5 N aqueous sodiumhydroxide, as necessary, and then sufficient water for injection isadded to provide a total volume of 20 mL. The mixture is then filteredthrough a sterile filter (0.22 micron) to provide a sterile solutionsuitable for administration by injection.

Exemplary Compositions for Administration by Inhalation

A compound of the invention (0.2 mg) is micronized and then blended withlactose (25 mg). This blended mixture is then loaded into a gelatininhalation cartridge. The contents of the cartridge are administeredusing a dry powder inhaler, for example.

Alternately, a micronized compound of the invention (10 g) is dispersedin a solution prepared by dissolving lecithin (0.2 g) in demineralizedwater (200 mL). The resulting suspension is spray dried and thenmicronized to form a micronized composition comprising particles havinga mean diameter less than about 1.5 μm. The micronized composition isthen loaded into metered-dose inhaler cartridges containing pressurized1,1,1,2-tetrafluoroethane in an amount sufficient to provide about 10 μgto about 500 mg of the compound of the invention per dose whenadministered by the inhaler.

Alternately, 25 mg of a compound of the invention is dissolved in 125 mLcitrate buffered (pH 5) isotonic saline. The mixture is stirred andsonicated until the compound is dissolved. The pH of the solution ischecked and adjusted, if necessary, to pH 5 by slowly adding aqueous 1NNaOH. The solution is administered using a nebulizer device thatprovides about 10 μg to about 500 μg of the compound of the inventionper dose.

EXAMPLES

The following Preparations and Examples are provided to illustratespecific embodiments of the invention. These specific embodiments,however, are not intended to limit the scope of the invention in any wayunless specifically indicated.

The following abbreviations have the following meanings unless otherwiseindicated and any other abbreviations used herein and not defined havetheir standard, generally accepted meaning:

ACE angiotensin converting enzyme AT₁ angiotensin II type 1 (receptor)AT₂ angiotensin II type 2 (receptor) BCA bicinchoninic acid BSA bovineserum albumin CDI N,N-carbonyldiimidazole DBU1,8-diazabicyclo-[5.4.0]undec-7-ene DCC N,N′-dicyclohexylcarbodiimideDCM dichloromethane (i.e., methylene chloride) DIPEAN,N-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethylsulfoxide Dnp 2,4-dinitrophenyl DOCA deoxycorticosterone acetate EDTAethylenediaminetetraacetic acid EGTA ethylene glycol bis(β-aminoethylether)-N,N,N′N′- tetraacetic acid EtOAc ethyl acetate HATUN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1- yl)uroniumhexafluorophosphate HOBt 1-hydroxybenzotriazole hydrate Mca(7-methoxycoumarin-4-yl)acyl MeCN acetonitrile MeOH methanol NEPneprilysin (EC 3.4.24.11) PBS phosphate buffered saline SHRspontaneously hypertensive rat TFA trifluoroacetic acid THFtetrahydrofuran Tris tris(hydroxymethyl)aminomethane Tween-20polyethylene glycol sorbitan monolaurate

Unless noted otherwise, all materials, such as reagents, startingmaterials and solvents, were purchased from commercial suppliers (suchas Sigma-Aldrich, Fluka Riedel-de Haën, and the like) and were usedwithout further purification.

Reactions were run under nitrogen atmosphere, unless noted otherwise.The progress of reactions were monitored by thin layer chromatography(TLC), analytical high performance liquid chromatography (anal. HPLC),and mass spectrometry, the details of which are given in specificexamples. Solvents used in analytical HPLC were as follows: solvent Awas 98% water/2% MeCN/1.0 mL/L TFA; solvent B was 90% MeCN/10% water/1.0mL/L TFA.

Reactions were worked up as described specifically in each preparationor example; commonly reaction mixtures were purified by extraction andother purification methods such as temperature-, and solvent-dependentcrystallization, and precipitation. In addition, reaction mixtures wereroutinely purified by preparative HPLC, typically using Microsorb C18and Microsorb BDS column packings and conventional eluents.Characterization of reaction products was routinely carried out by massand ¹H-NMR spectrometry. For NMR measurement, samples were dissolved indeuterated solvent (CD₃OD, CDCl₃, or DMSO-d₆), and ¹H-NMR spectra wereacquired with a Varian Gemini 2000 instrument (400 MHz) under standardobservation conditions. Mass spectrometric identification of compoundswas typically conducted using an electrospray ionization method (ESMS)with an Applied Biosystems (Foster City, Calif.) model API 150 EXinstrument or an Agilent (Palo Alto, Calif.) model 1200 LC/MSDinstrument.

Preparation 14′-(2-Butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonicAcid (2-aminoacetyl)amide.(C₂HF₃O₂)₂

4′-(2-Butyl-4-chloro-5-formylimidazol-1-ylmethyl)biphenyl-2-sulfonicacid t-butylamide (1a): To a DMF (75 mL) solution of4′-bromomethylbiphenyl-2-sulfonic acid t-butylamide (4.7 g, 12.2 mmol),was added 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (2.3 g, 12.2mmol) and potassium carbonate (1.7 g, 12.2 mmol). The mixture wasstirred at room temperature overnight. EtOAc (400 mL) was added and theorganic was washed 3 times with a sodium bicarbonate solution (200 mL)followed by saturated aqueous NaCl (200 mL). The solvent was removed andpurification was achieved by silica gel chromatography (50/50hexanes/EtOAc) using an isocratic gradient yielding intermediate (1a) asan off-white solid (5.0 g). Anal. HPLC: retention time=5.2 minutes.Gradient conditions: 10% solvent B/90% solvent A to 90% solvent B/10%solvent B over 6 minutes. MS m/z: [M+H]⁺ calcd for C₂₅H₃₀ClN₃O₃S,488.18; found 488.6.

4′-(2-Butyl-4-chloro-5-formylimidazol-1-ylmethyl)biphenyl-2-sulfonicacid amide.C₂HF₃O₂ (1b): TFA (10 mL, 129.8 mmol) was added tointermediate (1a) (5.0 g, 10.2 mmol). The mixture was stirred at 80° C.for 2 hours. TFA was removed under vacuum and the crude intermediate(1b), as a TFA salt, was used in the next step (5.6 g). Anal. HPLC:retention time=3.4 minutes. Gradient conditions: 25% solvent B/75%solvent A to 95% solvent B/5% solvent B over 6 minutes. MS m/z: [M+H]⁺calcd for C₂₁H₂₂ClN₃O₃S, 432.11; found 432.2.

{2-[4′-(2-Butyl-4-chloro-5-formylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-2-oxoethyl}carbamic acid t-butyl ester (1c): A THF solution (9 mL) of CDI (520 mg,3.2 mmol) was added to N-α-(t-butoxycarbonyl)glycine (562 mg, 3.2 mmol).The mixture was stirred at 80° C. for 1 hour, then cooled to roomtemperature. Intermediate (1b) (923 mg, 2.1 mmol) was added as a solidto the activated acid solution, followed by1,8-diazabicyclo[5.4.0]undec-7-ene (479 μL, 3.2 mmol). The mixture washeated to 80° C. with stirring for ˜2 hours. The mixture was cooled toroom temperature and EtOAc (200 mL) was added. The organic was washed 3times with a sodium bicarbonate solution (100 mL) followed by saturatedaqueous NaCl (100 mL). The solvent was removed and purification wasachieved by silica gel chromatography (1:2 hexanes:EtOAc) using anisocratic gradient to yield intermediate (1c) as a colorless semi-solid(738 mg). Anal. HPLC: retention time=4.6 minutes. Gradient conditions:25% solvent B/75% solvent A to 95° A solvent B/5° A solvent B over 6minutes. MS m/z: [M+H]⁺ calcd for C₂₈H₃₃ClN₄O₆S, 589.19; found 589.3.

{2-[4′-(2-Butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-2-oxoethyl}carbamicacid t-butyl ester (1d): To an ethanol (10 mL) solution of intermediate(1c) (738 mg, 1.25 mmol) was added solid sodium borohydride (62 mg, 1.6mmol). The mixture was stirred at room temperature for 1 hour. Aftercooling to 0° C., the reaction was quenched by dropwise addition of a50/50 solution of acetic acid/water until no effervescence was observed.EtOAc (100 mL) was added and the organic was washed 3 times withsaturated aqueous NaCl (100 mL) and dried over anhydrous Na₂SO₄. Thesolvent was removed to provide intermediate (1d) as a white solid (600mg). Anal. HPLC: retention time=3.3 minutes. Gradient conditions: 25%solvent B/75% solvent A to 95° A solvent B/5° A solvent B over 6minutes. MS m/z: [M+H]⁺ calcd for C₂₈H₃₅ClN₄O₆S, 591.20; found 591.2.

4′-(2-Butyl-4-chloro-5-hydroxymethyl-imidazol-1-ylmethyl)biphenyl-2-sulfonicacid (2-aminoacetyl)amide (1): To a DCM (500 μL) solution ofintermediate (1d) (600 mg, 1.0 mmol) was added TFA (500 μL, 6.4 mmol).The mixture was stirred at room temperature for 30 minutes. Volatileswere removed under vacuum and the TFA salt of the product waslyophilized in 50/50 water/acetonitrile to give the title compound as awhite solid (418 mg). Anal. HPLC: retention time=1.2 minutes. Gradientconditions: 25% solvent B/75% solvent A to 95% solvent B/5% solvent Bover 6 minutes. MS m/z: [M+H]⁺ calcd for C₂₃H₂₇ClN₄O₄S, 491.15; found473.1 [M+H]⁺−18.

EXAMPLE 12-Benzyl-N-{2-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-2-oxoethyl}-N′-hydroxymalonamide.(C₂HF₃O₂)

HATU (51 mg, 130 μmol) was added to a DMF (500 μL) solution ofN-acetoxy-2-benzyl-malonamic acid (30 mg, 120 μmol), and the solutionwas stirred for 15 minutes at room temperature.4′-(2-Butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonicacid (2-aminoacetyl)amide.(C₂HF₃O₂)₂ (96 mg, 1.3 mmol) was added as aDMF solution (500 μL) and the mixture was stirred for 2.5 hours. MeOH(500 μL) and 10N NaOH (500 μL) were added to the crude mixture, whichwas then stirred at room temperature for 2 hours. Volatiles were removedunder vacuum and the crude oil was further purified by preparative HPLC(reverse phase) on a gradient of 10-90% (5-10% over 10 min; 10-90% over50 min); flow rate 15 mL/min; detection at 280 nm. Pure fractions werecombined and lyophilized in 50/50 water/acetonitrile to give the titlecompound as a white solid (4.4 mg). Anal. HPLC: retention time=3.7minutes. Gradient conditions 90% solvent B/10% solvent A to 10% solventB/90% solvent B over 6 minutes. MS m/z: [M+H]⁺ calcd for C₃₃H₃₆ClN₅O₇S,682.21; found 682.4.

EXAMPLE 2

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds2-1 to 2-32, having the following formula, were also prepared:

Ex. X R¹ R² R⁵ R⁶ R⁷ 2-1 —SO₂NHC(O)(CH₂)₂— —CH₂OH Cl —CH₂—SH —CH₂- HNHC(O)—CH₂—NHC(O)— phenyl 2-2 —SO₂NHC(O)(CH₂)₆— —CH₂OH Cl —CH₂—SH —CH₂-H NHC(O)—CH₂—NHC(O)— phenyl 2-3 —SO₂NHC(O)(CH₂)₂— —CH₂OH Cl —CH₂—SH—CH₂- H NHC(O)— phenyl 2-4 —SO₂NHC(O)(CH₂)₂— —CH₂OH Cl —SH —CH₂- HNHC(O)— phenyl 2-5 —SO₂NHC(O)(CH₂)₂— —CH₂OH Cl —C(O)NH—(OH) —CH₂- HNHC(O)—CH₂—NHC(O)— phenyl 2-6 —SO₂NHC(O)(CH₂)₄— —CH₂OH Cl —CH₂—SH —CH₂-H NHC(O)— phenyl 2-7 —SO₂—NHC(O)(CH₂)₄— —CH₂OH Cl —C(O)NH—(OH) —CH₂- HNHC(O)—CH₂—NHC(O)— phenyl 2-8 —SO₂—NHC(O)(CH₂)₆— —CH₂OH Cl —CH₂—SH —CH₂-H NHC(O)— phenyl 2-9 —SO₂NHC(O)(CH₂)₆— —CH₂OH Cl —C(O)NH—(OH) —CH₂- HNHC(O)—CH₂—NHC(O)— phenyl 2-10 —SO₂NHC(O)(CH₂)₄— —CH₂OH Cl —SH —CH₂- HNHC(O)— phenyl 2-11

—CH₂OH Cl —CH₂—CH— [CH₂O(CH₂)₂— OCH₃]—COOH taken together with R⁷ toform cyclopentyl 2-12

—CH₂OH Cl —CH₂—CH— [CH₂O(CH₂)₂— OCH₃]—COOH taken together with R⁷ toform cyclopentyl 2-13 —SO₂NHC(O)CH₂—NH— —CH₂OH H —C(O)NH—(OH) —CH₂- HC(O)—CH₂—NHC(O)— phenyl 2-14 —SO₂NHC(O)(CH₂)₂— —CH₂OH Cl —C(O)NH—(OH)—CH₂- H NHC(O)—CH₂— phenyl CH(COOH)—NHC(O)— 2-15 —SO₂NHC(O)(CH₂)₂——CH₂OH Cl —C(O)NH—(OH) —CH₂- H NHC(O)—CH₂—CH(COOH)— phenyl NHC(O)— 2-16—SO₂NHC(O)(CH₂)₂— —CH₂OH Cl —C(O)NH—(OH) —CH₂- H NHC(O)—(CH₂)₂— phenylCH(COOH)—NHC(O)— 2-17 —SO₂NHC(O)CH₂— —CH₂OH Cl —CH₂—SH —CH₂- H NHC(O)—phenyl 2-18 —SO₂NHC(O)CH₂— —CH₂OH Cl —SH —CH₂- H NHC(O)— phenyl 2-19—SO₂NHC(O)CH₂— —COOH Cl —C(O)NH—(OH) —CH₂- H NHC(O)— phenyl 2-20—SO₂NHC(O)CH₂— —CH₂OH Cl —NH—CH₂— —CH₂- H NHC(O)— P(O)(OH)₂ biphenyl2-21 —SO₂NHC(O)CH₂— —CH₂OH Cl —CH₂—SH —CH— H NHC(O)— (CH₃)₂ 2-22—SO₂NHC(O)CH₂— —CH₂OH Cl —CH₂—SH —CH₂- H NHC(O)—CH₂—NHC(O)— phenyl 2-23—SO₂NHC(O)CH₂— —CH₂OH Cl —CH₂—SH —CH₃ H NHC(O)— 2-24 —SO₂NHC(O)CH₂——CH₂OH Cl —C(O)NH—(OH) —CH₂— H NHC(O)— CH— (CH₃)₂ 2-25 —SO₂NHC(O)CH₂——CH₂OH Cl —CH₂—SH —CH₃ H NHC(O)— 2-26 —SO₂NHC(O)CH₂— —CH₂OH Cl —C(O)NH——CH₂— H NHC(O)— [OC(O)C(CH₃)₃] CH— (CH₃)₂ 2-27 —SO₂NHC(O)CH[CH— —CHO Cl—CH₂—SH —CH₂- H (CH₃)₂]—NHC(O)— phenyl 2-28 —SO₂NHC(O)CH[CH— —CHO Cl—C(O)NH—(OH) —CH₂— H (CH₃)₂]—NHC(O)— CH(CH₃)₂ 2-29 —SO₂NHC(O)CH[CH— —CHOCl —C(O)NH—(OH) —CH₂- H (CH₃)₂]—NHC(O)— phenyl 2-30 —SO₂NHC(O)CH₂——CH₂OH Cl —C(O)NH— —CH₂- H NHC(O)— [OC(O)CH₃] phenyl 2-31

—CHO Cl —C(O)NH—(OH) —CH₂- phenyl H 2-32

—CHO Cl —C(O)NH—(OH) —CH₂— CH— (CH₃)₂ H

-   (2-1)    2-benzyl-N-({3-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)-biphenyl-2-sulfonylamino]-3-oxopropylcarbamoyl)methyl)-3-mercaptopropionamide.    MS m/z: [M+H]⁺ calcd for C₃₆H₄₂ClN₅O₆S₂, 740.23; found 740.2.-   (2-2)    2-benzyl-N-({7-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)-biphenyl-2-sulfonylamino]-7-oxoheptylcarbamoyl)methyl)-3-mercaptopropionamide.    MS m/z: [M+H]⁺ calcd for C₄₀H₅₀ClN₅O₆S₂, 796.29; found 796.2.-   (2-3)    N-{3-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-3-oxopropyl}-2-mercaptomethyl-3-phenylpropionamide.    MS m/z: [M+H]⁺ calcd for C₃₄H₃₉ClN₄O₅S₂, 683.21; found 683.2.-   (2-4)    (S)—N-{3-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-3-oxopropyl}-2-mercapto-3-phenylpropionamide.    MS m/z: [M+H]⁺ calcd for C₃₃H₃₇ClN₄O₅S₂, 669.19; found 670.2.-   (2-5)    2-benzyl-N-({3-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)-biphenyl-2-sulfonylamino]-3-oxopropylcarbamoyl)methyl)-N′-hydroxymalonamide.    MS m/z: [M+H]⁺ calcd for C₃₆H₄₁ClN₅O₈S, 753.24; found 753.2.-   (2-6)    N-{5-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-5-oxopentyl}-2-mercaptomethyl-3-phenylpropionamide.    MS m/z: [M+H]⁺ calcd for C₃₆H₄₃ClN₄O₅S₂, 711.24; found 711.2.-   (2-7)    2-benzyl-N-({5-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)-biphenyl-2-sulfonylamino]-5-oxopentylcarbamoyl)methyl)-N′-hydroxymalonamide.    MS m/z: [M+H]⁺ calcd for C₃₈H₄₅ClN₆O₈S, 781.27; found 781.2.-   (2-8)    N-{7-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-7-oxoheptyl}-2-mercaptomethyl-3-phenylpropionamide.    MS m/z: [M+H]⁺ calcd for C₃₈H₄₇ClN₄O₅S₂, 739.27; found 739.4.-   (2-9)    2-benzyl-N-({7-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)-biphenyl-2-sulfonylamino]-7-oxoheptylcarbamoyl)methyl)-N′-hydroxymalonamide.    MS m/z: [M+H]⁺ calcd for C₄₀H₄₉ClN₆O₈S, 809.30; found 809.2.-   (2-10)    (S)—N-{5-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-5-oxopentyl}-2-mercapto-3-phenylpropionamide.    MS m/z: [M+H]⁺ calcd for C₃₅H₄₁ClN₄O₅S₂, 697.22; found 697.2.-   (2-11)    3-(1-{4-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylaminocarbonyl]cyclohexylcarbamoyl}cyclopentyl)-2-(2-methoxyethoxymethyl)-propionic    acid. MS m/z: [M+H]⁺ calcd for C₄₁H₅₅ClN₄O₉S, 815.34; found 815.7.-   (2-12)    3-[1-(4-{3-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-3-oxopropylcarbamoyl}-cyclohexylcarbamoyl)-cyclopentyl]-2-(2-methoxyethoxymethyl)propionic    acid. MS m/z: [M+H]⁺ calcd for C₄₄H₆₀ClN₅O₁₀S, 886.38; found 886.8.-   (2-13)    2-benzyl-N-({3-[4′-(2-butyl-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-3-oxopropylcarbamoyl)methyl)-N′-hydroxymalonamide.    MS m/z: [M+H]⁺ calcd for C₃₆H₄₂N₆O₈S, 719.28; found 719.5.-   (2-14)    (R)—N-{3-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)-biphenyl-2-sulfonylamino]-3-oxopropyl}-2-(2-hydroxycarbamoyl-3-phenylpropionyl-amino)succinamic    acid. MS m/z: [M+H]⁺ calcd for C₃₈H₄₃ClN₆O₁₀S, 811.25; found 811.5.-   (2-15)    (R)—N-{3-[4′-(2-butyl-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-3-oxopropyl}-2-(2-hydroxycarbamoyl-3-phenylpropionylamino)succinamic    acid. MS m/z: [M+H]⁺ calcd for C₃₈H₄₄N₆O₁₀S, 777.28; found 777.5.-   (2-16)    (R)-4-{3-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-3-oxopropylcarbamoyl}-2-(2-hydroxycarbamoyl-3-phenylpropionyl-amino)butyric    acid. MS m/z: [M+H]⁺ calcd for C₃₉H₄₅ClN₆O₁₀S, 825.26; found 825.5.-   (2-17)    N-{2-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-2-oxoethyl}-2-mercaptomethyl-3-phenylpropionamide.    MS m/z: [M+H]⁺ calcd for C₃₃H₃₇ClN₄O₅S₂, 669.19; found 669.3.-   (2-18)    (S)—N-{2-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-2-oxo    ethyl}-2-mercapto-3-phenylpropionamide. MS Tn/z: [M+H]⁺ calcd for    C₃₂H₃₅ClN₄O₅S₂, 655.17; found 655.2.-   (2-19)    2-butyl-5-chloro-3-{2′-[2-(2-hydroxycarbamoyl-3-phenylpropionylamino)-acetylsulfamoyl]biphenyl-4-ylmethyl}-3H-imidazole-4-carboxylic    acid. MS m/z: [M+H]⁺ calcd for C₃₃H₃₄ClN₅O₈S, 696.18; found 696.3.-   (2-20)    [((S)-2-biphenyl-4-yl-1-{2-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-2-oxoethylcarbamoyl}ethylamino)methyl]phosphonic    acid. MS m/z: [M+H]⁺ calcd for C₃₉H₄₃ClN₅O₈PS, 808.23; found 808.4.-   (2-21)    N-{2-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-2-oxoethyl}-2-mercaptomethyl-3-methylbutyramide.    MS m/z: [M+H]⁺ calcd for C₂₉H₃₇ClN₄O₅S₂, 621.19; found 621.5.-   (2-22)    2-benzyl-N-({2-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)-biphenyl-2-sulfonylamino]-2-oxoethylcarbamoyl)methyl)-3-mercaptopropionamide.    MS m/z: [M+H]⁺−18 calcd for C₃₅H₄₀ClN₅O₆S₂, 726.21; found 708.4.-   (2-23)    (R)—N-{2-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)-biphenyl-2-sulfonylamino]-2-oxoethyl}-3-mercapto-2-methylpropionamide.    MS m/z: [M+H]⁺−18 calcd for C₂₇H₃₃ClN₄O₅S₂, 593.16; found 575.2.-   (2-24)    N-{2-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-2-oxoethyl}-N′-hydroxy-2-isobutylmalonamide.    MS m/z: [M+H]⁺ calcd for C₃₀H₃₈ClN₅O₇S, 648.22; found 648.4.-   (2-25)    N-{2-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-2-oxoethyl}-3-mercapto-2-methylpropionamide.    MS m/z: [M+H]⁺ calcd for C₂₇H₃₃ClN₄O₅S₂, 593.16; found 593.5.-   (2-26)    N-{2-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-2-oxo    ethyl}-N′-(2,2-dimethylpropionyloxy)-2-isobutylmalonamide. MS m/z:    [M+H]⁺ calcd for C₃₅H₄₆ClN₅O₈S, 732.28; found 732.2.-   (2-27)    2-benzyl-N-{(R)-1-[4′-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)-biphenyl-2-sulfonylaminocarbonyl]-2-methylpropyl}-3-mercaptopropionamide.    MS m/z: [M+H]⁺ calcd for C₃₆H₄₁ClN₄O₅S₂, 709.22; found 709.4.-   (2-28)    N-{(R)-1-[4′-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)biphenyl-2-sulfonylaminocarbonyl]-2-methylpropyl}-N′-hydroxy-2-isobutylmalonamide.    MS m/z: [M+H]⁺ calcd for C₃₃H₄₂ClN₅O₇S, 688.25; found 688.2.-   (2-29)    2-benzyl-N-{(R)-1-[4′-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)-biphenyl-2-sulfonylaminocarbonyl]-2-methylpropyl}-N′-hydroxymalonamide.    MS m/z: [M+H]⁺ calcd for C₃₆H₄₀ClN₅O₇S, 722.23; found 722.3.-   (2-30)    N-acetoxy-2-benzyl-N′-{2-[4′-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)biphenyl-2-sulfonylamino]-2-oxoethyl}-malonamide.    MS m/z: [M+H]⁺ calcd for C₃₅H₃₈ClN₅O₈S, 724.21; found 724.4.-   (2-31)    2-benzyl-N-{(1R,3S)-3-[4′-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)-biphenyl-2-sulfonylaminocarbonyl]cyclopentyl}-N′-hydroxymalonamide.    MS m/z: [M+H]⁺+1 calcd for C₃₇H₄₀ClN₅O₇S, 734.23; found 735.4-   (2-32)    N-{(1R,3S)-3-[4′-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)-biphenyl-2-sulfonylaminocarbonyl]cyclopentyl}-N′-hydroxy-2-isobutylmalonamide.    MS m/z: [M+H]⁺+1 calcd for C₃₄H₄₂ClN₅O₇S, 700.25; found 701.4.

Preparation 2N-(2-Aminoacetyl)-4-(2-butyl-4-chloro-5-formyl-imidazol-1-ylmethyl)benzenesulfonamide

4-Bromomethyl-N-t-butyl-benzenesulfonamide (2a): t-Butyl amine (5.9 mL,56 mmol, 1.0 eq) and DIPEA (9.7 mL, 56 mmol, 1.0 eq) were added to 350ml DCM. The solution was cooled to 0° C. and a solution of4-bromomethylbenzenesulfonyl chloride (15.1 g, 56 mmol, 1.0 eq) in 100mL DCM was added drop-wise via an addition funnel. The mixture was thenslowly warmed to room temperature and stirred for 3 hours. The mixturewas concentrated under reduced pressure and the residue was dissolvedinto 350 mL EtOAc. The organic was washed with 1N aq. HCl, saturatedbicarbonate, water, saturated aqueous NaCl, dried over MgSO₄, andfiltered. The filtrate was concentrated to yield intermediate (2a) (13.6g).

N-t-butyl-4-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)benzenesulfonamide(2b): Intermediate (2a) (13.6 g, 45 mmol, 1.0 eq),2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (8.4 g, 45 mmol, 1.0 eq)and potassium carbonate (12.4 g, 90 mmol, 2.0 eq) were added to 90 mL ofDMF. The mixture was stirred at room temperature for 16 hours. Themixture was then diluted with 300 mL EtOAc and extracted with 100 mL 10%aq. LiCl, 2×200 mL water, 100 mL saturated aqueous NaCl, dried overMgSO₄, and filtered. The filtrate was evaporated and purified by flashchromatography (40% EtOAc:hexanes) to yield intermediate (2b) (13.0 g).MS m/z: [M+H⁺] calcd for C₁₉H₂₆ClN₃O₃S, 412.1; found 412.4.

4-(2-Butyl-4-chloro-5-formyl-imidazol-1-ylmethyl)benzenesulfonamide(2c): Intermediate (2b) was dissolved into 60 mL of 1:1 DCM:TFA andheated to 40° C. for 16 hours. The mixture was concentrated underreduced pressure to yield intermediate (2c) as a yellow oil in aquantitative yield. MS m/z: [M+H⁺] calcd for C₁₅H₁₈ClN₃O₃S 356.1; found356.3.

{2-[4-(2-Butyl-4-chloro-5-formylimidazol-1-ylmethyl)benzenesulfonylamino]-2-oxoethyl}carbamicacid t-butyl ester (2d): N-Boc-glycine (2.8 g, 16 mmol, 1.0 eq) wasdissolved into 50 mL THF. CDI (2.6 g, 16 mmol, 1.0 eq) was added, andthe mixture heated to 80° C. for 2 hours. The solution was cooled toroom temperature and added to a solution of intermediate (2c) (5.7 g, 16mmol, 1.0 eq) in 100 mL THF followed by DBU (2.4 mL, 16 mmol, 1.0 eq).The mixture was stirred at room temperature overnight. The mixture wasthen concentrated, redissolved into 100 mL EtOAc, washed with saturatedbicarbonate, saturated aqueous NaCl, dried over MgSO₄, and evaporated.The residue was chromatographed (10% MeOH:EtOAc with 0.7% NH₃) to yieldintermediate (2d) (5.6 g).

N-(2-Aminoacetyl)-4-(2-butyl-4-chloro-5-formyl-imidazol-1-ylmethyl)benzenesulfonamide(2): Intermediate (2d) (5.6 g) was dissolved into 20 mL 30% TFA:DCM andstirred at room temperature for 2 hours. The mixture was concentratedunder reduced pressure to yield the title compound as an oil in aquantitative yield. MS m/z: [M+H⁺] calcd for C₁₇H₂₁ClN₄O₄S 413.1; found413.3.

Preparation 3 2-(2,2-Dimethylpropionyloxycarbamoyl)-4-methylpentanoicAcid

2-Isobutylmalonic acid monoethyl ester (3a): 2-Isobutylmalonic acidethyl ester methyl ester (50.0 g, 231 mmol, 1.0 eq) was dissolved into280 ml ethanol. To this solution was added solid KOH (12.7 g, 226 mmol,0.98 eq) and the mixture was stirred at room temperature for 16 hours.The mixture was then concentrated under reduced pressure and redissolvedin 500 mL water. The solution was washed 2×250 ml diethyl ether,acidified to pH 2 with 6N HCl, and extracted with 2×250 mL diethylether. The organic was dried over MgSO₄, and concentrated to yieldintermediate (3a) (40.3 g). ¹H NMR (DMSO) δ (ppm): 1.0 (dd, 6H), 1.2 (t,1H), 1.3 (t, 3H), 1.5-1.7 (m, 1H), 1.8 (t, 2H), 3.5 (m, 2H), 4.2 (quart,2H).

2-Benzyloxycarbamoyl-4-methylpentanoic acid ethyl ester (3b):Intermediate (3a) (40.3 g, 214 mmol, 1.0 eq) was dissolved into 800 mLDCM and 900 mL THF and the solution was cooled to 0° C. To this wasadded benzyl hydroxylamine (34.2 g, 214 mmol, 1.0 eq) followed by HOBt(28.9 g, 214 mmol, 1.0 eq). The mixture was stirred for 5 minutes, thenDCC (44.1 g, 214 mmol, 1.0 eq) was added, followed by triethylamine(33.4 mL, 240 mmol, 1.1 eq). The mixture was warmed to room temperatureand stirred overnight. The solid was filtered and the filtrate wasconcentrated. The material was redissolved in 1000 mL EtOAc and washedwith 500 mL 1N HCl, 600 mL saturated aq. bicarbonate, dried over MgSO₄,filtered, and evaporated to yield intermediate (3b) (59.3 g) as asemisolid. MS m/z: [M+H⁺] calcd for C₁₆H₂₃NO₄ 294.2; found 294.2.

2-Benzyloxycarbamoyl-4-methyl-pentanoic acid (3c): Intermediate (3b)(7.5 g, 25.5 mmol, 1.0 eq) was dissolved into 80 mL of 1N NaOH solutionand stirred at room temperature overnight. The solution was then washedwith 80 mL EtOAc, acidified to pH 1 with 6N HCl and extracted 2×100 mLEtOAc. The organic was dried over MgSO₄ and concentrated to yieldintermediate (3c) (6.6 g). ¹H NMR (DMSO) δ (ppm): 1.0 (m, 6H), 1.4-1.8(m, 3H), 1.3 (t, 3H), 1.5-1.7 (m, 1H), 3.2 (t, 1H), 4.9 (s, 2H), 7.4-7.6(m, 5H) 11.4 (s, 1H).

2-Hydroxycarbamoyl-4-methylpentanoic acid (3d): Intermediate (3c) (6.6g, 24.7 mmol) was dissolved into 75 mL ethanol and the solution wasdegassed with nitrogen. To the solution was added 1.3 g (20% by weight)Pd/C (10% by weight, wet) and the reaction was degassed under hydrogen.After 16 hours, the mixture was filtered through celite and the ethanolwas removed in vacuo to yield intermediate (3d) (4.3 g) as a pink oil.¹H NMR (DMSO) δ (ppm): 0.7 (m, 6H), 1.2-1.4 (m, 1H), 1.4-1.6 (m, 2H),2.9 (t, 1H), 3.3 (quart, 1H), 8.9 (br s, 1H), 10.5 (br s, 1H).

2-(2,2-Dimethylpropionyloxycarbamoyl)-4-methylpentanoic acid (3):Intermediate (3d) (12.7 g, 73.2 mmol, 1.0 eq) was dissolved into 180 mLDCM and cooled to 0° C. DIPEA (13.4 mL, 76.9 mmol, 1.05 eq) was added,followed by pivaloyl chloride (9.5 mL, 76.9 mmol, 1.05 eq). The mixturewas warmed to room temperature and stirred for 12 hours. The mixture wasconcentrated under reduced pressure, dissolved into 300 mL EtOAc, washed2×200 mL 1M H₃PO₄, 100 mL saturated aqueous NaCl, dried over MgSO₄, andevaporated. The material was triturated with hexanes, filtered and driedthe to yield the title compound (10.5 g, 55%). ¹H NMR (DMSO) δ (ppm):0.7 (m, 6H), 1.2-1.4 (m, 1H), 1.4-1.6 (m, 2H), 2.9 (t, 1H), 3.3 (quart,1H), 8.9 (br s, 1H), 10.5 (br s, 1H).

EXAMPLE 3N-(2-{4-[2-Butyl-4-chloro-5-(2-thiophen-2-ylethylcarbamoyl)imidazol-1-ylmethyl]benzenesulfonylamino}-2-oxoethyl)-N′-hydroxy-2-isobutylmalonamide

N-{2-[4-(2-Butyl-4-chloro-5-formylimidazol-1-ylmethyl)benzenesulfonylamino]-2-oxoethyl}-N′-(2,2-dimethylpropionyloxy)-2-isobutylmalonamide(3a):N-(2-Aminoacetyl)-4-(2-butyl-4-chloro-5-formyl-imidazol-1-ylmethyl)benzenesulfonamide(770 mg, 1.2 mmol, 1.0 eq) and2-(2,2-Dimethylpropionyloxycarbamoyl)-4-methylpentanoic acid (360 mg,1.2 mmol, 1.0 eq) were dissolved in 13 mL DMF. HATU (460 mg, 1.2 mmol,1.0 eq) was then added followed by DIPEA (630 μL, 3.6 mmol, 3.0 eq) andthe mixture was stirred at room temperature. After 3 hours, the mixturewas diluted with 30 mL EtOAc, washed with 20 mL 10% aq. LiCl solution,water, saturated aqueous NaCl, dried over MgSO₄, filtered, andconcentrated under reduced pressure to yield crude intermediate 3a. MSm/z: [M+H⁺] calcd for C₂₉H₄₀ClN₅O₈S, 654.2; found 654.4.

2-Butyl-5-chloro-3-(4-{2-[2-(2,2-dimethylpropionyloxycarbamoyl)-4-methylpentanoylamino]acetylsulfamoyl}benzyl)-3H-imidazole-4-carboxylicacid (3b): The crude intermediate (A) was dissolved in 18 mL n-butanol.To this was added 2-methyl-2-butene (2.0M in THF, 1.2 mL, 2.3 mmol, 11.2eq). A solution of NaClO₂ (1.1 g, 11.6 mmol, 10.6 eq) and NaH₂PO₄ (1.1g, 8.8 mmol, 8.6 eq) in 24 mL water was then added and the mixture wasstirred at room temperature. After 5 hours, the mixture reaction wasdiluted with 30 mL EtOAc and washed 2×20 mL Na₂SO₃. The organic layerwas dried over MgSO₄, filtered, and concentrated to yield intermediate3b (660 mg). MS m/z: [M+H⁺] calcd for C₂₉H₄₀ClN₅O₉S, 670.2; found 670.4.

Intermediate 3b (67 mg, 0.1 mmol, 1.0 eq) was dissolved into 1 mL DMF.To this was added HATU (38 mg, 0.1 mmol, 1.0 eq), 2-thiophene ethylamine(12 μL, 0.1 mmol, 1.0 eq), and DIPEA (17 μL, 0.1 mmol, 1.0 eq.). Themixture was stirred for 3 hours and was then concentrated in vacuo. Thematerial was redissolved in 1.0 mL methanol and to this was added 1.0 mLaq. 3N NaOH. The mixture was stirred for 4 hours, then acidified with0.5 mL acetic acid and concentrated under reduced pressure. Theresulting material was purified by preparative HPLC and lyophilized toyield the title compound as a white powder. MS m/z: [M+H⁺] calcd forC₃₀H₃₉ClN₆O₇S₂, 696.2; found 696.2.

EXAMPLE 4

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds4-1 to 4-19, having the following formula, were also prepared:

Ex. X R¹ R⁵ R⁶ 4-1 —SO₂NHC(O)CH₂— —CHO —SH —CH(CH₃)CH₂CH₃ NHC(O)— 4-2—SO₂NHC(O)CH₂— —CHO —C(O)NH(OH) —CH₂—CH(CH₃)₂ NHC(O)— 4-3 —SO₂NHC(O)CH₂——CH₂OH —SH —CH₂-phenyl NHC(O)— 4-4 —SO₂NHC(O)CH₂— —CH₂OH —C(O)NH(OH)—CH₂—CH(CH₃)₂ NHC(O)— 4-5 —SO₂NHC(O)CH₂— —CH₂OH —C(O)NH(OH) —CH₂-phenylNHC(O)— 4-6 —SO₂NHC(O)(CH₂)₂— —CHO —SH —CH(CH₃)CH₂CH₃ NHC(O)— 4-7—SO₂NHC(O)(CH₂)₂— —CHO —C(O)NH(OH) —CH₂-phenyl NHC(O)— 4-8—SO₂NHC(O)(CH₂)₂— —CHO —C(O)NH(OH) —CH₂—CH(CH₃)₂ NHC(O)— 4-9—SO₂NHC(O)(CH₂)₂— —CH₂OH —SH —CH₂-phenyl NHC(O)— 4-10 —SO₂NHC(O)(CH₂)₂——CH₂OH —SH —CH(CH₃)CH₂CH₃ NHC(O)— 4-11 —SO₂NHC(O)(CH₂)₂— —CH₂OH—C(O)NH(OH) —CH₂-phenyl NHC(O)— 4-12 —SO₂NHC(O)(CH₂)₂— —CH₂OH—C(O)NH(OH) —CH₂—CH(CH₃)₂ NHC(O)— 4-13 —SO₂NHC(O)CH₂— —COOH —C(O)NH(OH)—CH₂—CH(CH₃)₂ NHC(O)— 4-14 —SO₂NHC(O)CH₂— —C(O)NHCH₂- —C(O)NH(OH)—CH₂—CH(CH₃)₂ NHC(O)— phenyl 4-15 —SO₂NHC(O)CH₂— —CH₂— —C(O)NH(OH)—CH₂—CH(CH₃)₂ NHC(O)— NHCH(COOH)— CH₂—CH(CH₃)₂ 4-16 —SO₂NHC(O)CH₂——C(O)NHCH₂- —C(O)NH(OH) —CH₂—CH(CH₃)₂ NHC(O)— thiophen-2-yl 4-17—SO₂NHC(O)CH₂— —C(O)NH(CH₂)₃- —C(O)NH(OH) —CH₂—CH(CH₃)₂ NHC(O)— phenyl4-18 —SO₂NHC(O)CH₂— —C(O)NH(CH₂)₄- —C(O)NH(OH) —CH₂—CH(CH₃)₂ NHC(O)—phenyl 4-19 —SO₂NHC(O)CH₂— —C(O)NH(CH₂)₂- —C(O)NH(OH) —CH₂—CH(CH₃)₂NHC(O)— phenyl

-   (4-1) 2-mercapto-3-methylpentanoic acid    {2-[4-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)-benzenesulfonylamino]-2-oxoethyl}    amide. MS m/z: [M+H]⁺+1 calcd for C₂₁H₁₁ClN₄O₅S₂, 543.14; found    542.2.-   (4-2)    N-{2-[4-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)benzenesulfonyl-amino]-2-oxoethyl}-N′-hydroxy-2-isobutylmalonamide.    MS m/z: [M+H]⁺ calcd for C₂₄H₃₂ClN₅O₇S, 570.17; found 570.2.-   (4-3)    (S)—N-{2-[4-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)-benzenesulfonylamino]-2-oxoethyl}-2-mercapto-3-phenylpropionamide.    MS m/z: [M+H]⁺ calcd for C₂₆H₃₁ClN₄O₅S₂, 579.14; found 579.-   (4-4)    N-{2-[4-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)-benzenesulfonylamino]-2-oxoethyl}-N′-hydroxy-2-isobutylmalonamide.    MS m/z: [M+H]⁺ calcd for C₂₄H₃₄ClN₅O₇S, 572.19; found 572.2.-   (4-5)    2-benzyl-N-{2-[4-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)benzenesulfonylamino]-2-oxoethyl}-N′-hydroxymalonamide.    MS m/z: [M+H]⁺ calcd for C₂₇H₃₂ClN₅O₇S, 606.17; found 606.-   (4-6) 2-mercapto-3-methylpentanoic acid    {3-[4-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)-benzenesulfonylamino]-3-oxopropyl}    amide. MS m/z: [M+H]⁺ calcd for C₂₄H₃₃ClN₄O₅S₂, 557.16; found 557.2.-   (4-7)    2-benzyl-N-{3-[4-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)-benzenesulfonylamino]-3-oxopropyl}-N′-hydroxymalonamide.    MS m/z: [M+H]⁺ calcd for C₂₈H₃₂ClN₅O₇S, 618.17; found 618.-   (4-8)    N-{3-[4-(2-butyl-4-chloro-5-formylimidazol-1-ylmethyl)benzenesulfonyl-amino]-3-oxopropyl}-N′-hydroxy-2-isobutylmalonamide.    MS m/z: [M+H]⁺+1 calcd for C₂₅H₃₄ClN₅O₇S, 584.19; found 585.2.-   (4-9)    (S)—N-{3-[4-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)benzene-sulfonylamino]-3-oxopropyl}-2-mercapto-3-phenylpropionamide.    MS m/z: [M+H]⁺ calcd for C₂₇H₃₃ClN₄O₅S₂, 593.16; found 593.2.-   (4-10) 2-mercapto-3-methylpentanoic acid    {3-[4-(2-butyl-4-chloro-5-hydroxymethyl-imidazol-1-ylmethyl)benzenesulfonylamino]-3-oxopropyl}amide.    MS m/z: [M+H]⁺ calcd for C₂₄H₃₅ClN₄O₅S₂, 559.17; found 559.-   (4-11)    2-benzyl-N-{3-[4-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)-benzenesulfonylamino]-3-oxopropyl}-N′-hydroxymalonamide.    MS m/z: [M+H]⁺ calcd for C₂₈H₃₄ClN₅O₇S, 620.19; found 620.-   (4-12)    N-{3-[4-(2-butyl-4-chloro-5-hydroxymethylimidazol-1-ylmethyl)benzene-sulfonylamino]-3-oxopropyl}-N′-hydroxy-2-isobutylmalonamide.    MS m/z/z: [M+H]⁺ calcd for C₂₅H₃₆ClN₅O₇S, 586.20; found 586.-   (4-13)    2-butyl-5-chloro-3-{4-[2-(2-hydroxycarbamoyl-4-methylpentanoylamino)-acetylsulfamoyl]benzyl}-3H-imidazole-4-carboxylic    acid. MS m/z: [M+H]⁺ calcd for C₂₄H₃₂ClN₅O₈S, 586.17; found 586.-   (4-14)    N-{2-[4-(5-benzylcarbamoyl-2-butyl-4-chloroimidazol-1-ylmethyl)benzene-sulfonylamino]-2-oxoethyl}-N′-hydroxy-2-isobutylmalonamide.    MS m/z: [M+H]⁺ calcd for C₃₁H₃₉ClN₆O₇S, 675.23; found 675.0.-   (4-15)    (S)-2-[(2-butyl-5-chloro-3-{4-[2-(2-hydroxycarbamoyl-4-methylpentanoyl-amino)acetylsulfamoyl]-benzyl}-3H-imidazol-4-ylmethyl)-amino]-4-methylpentanoic    acid. MS m/z: [M+H]⁺ calcd for C₃₀H₄₅ClN₆O₈S, 685.27; found 685.4.-   (4-16)    N-[2-(4-{2-butyl-4-chloro-5-[(thiophen-2-ylmethyl)carbamoyl]-imidazol-1-ylmethyl}benzenesulfonylamino)-2-oxoethyl]-N′-hydroxy-2-isobutyl-malonamide.    MS m/z: [M+H]⁺ calcd for C₂₉H₃₇ClN₆O₇S₂, 681.19; found 681.3.-   (4-17)    N-(2-{4-[2-butyl-4-chloro-5-(3-phenyl-propylcarbamoyl)imidazol-1-ylmethyl]-benzenesulfonylamino}-2-oxoethyl)-N′-hydroxy-2-isobutylmalonamide.    MS m/z: [M+H]⁺+1 calcd for C₃₃H₄₃ClN₆O₇S, 703.26; found 704.4.-   (4-18)    N-(2-{-4-[2-butyl-4-chloro-5-(4-phenyl-butylcarbamoyl)imidazol-1-ylmethyl]-benzenesulfonylamino}-2-oxoethyl)-N′-hydroxy-2-isobutylmalonamide.    MS m/z: [M+H]⁺+1 calcd for C₃₄H₄₅ClN₆O₇S, 717.28; found 718.-   (4-19)    N-{2-[4-(2-butyl-4-chloro-5-phenethylcarbamoylimidazol-1-ylmethyl)benzene-sulfonylamino]-2-oxoethyl}-N′-hydroxy-2-isobutylmalonamide.    MS m/z: [M+H]⁺ calcd for C₃₂H₄₁ClN₆O₇S, 689.24; found 689.0.

EXAMPLE 5

Following the procedures described in the examples above, andsubstituting 2-butyl-1,3-diaza-spiro[4.4]non-1-en-4-one for2-butyl-5-chloro-3H-imidazole-4-carbaldehyde in Preparation 1, as wellas substituting the appropriate starting materials and reagents,compounds 5-1 to 5-3, having the following formula, were also prepared:

Ex. X R⁵ R⁶ 5-1 —SO₂NHC(O)CH[CH(CH₃)₂]— —C(O)NH(OH) —CH₂-phenyl NHC(O)—5-2 —SO₂NHC(O)CH₂—NHC(O)— —C(O)NH(OH) —CH₂-phenyl 5-3 —SO₂NHC(O)— —SH—CH₂— CH(CH₃)₂

-   (5-1)    2-benzyl-N-{2-[4′-(2-butyl-4-oxo1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)-biphenyl-2-sulfonylamino]-2-oxoethyl}-N′-hydroxymalonamide.    MS m/z: [M+H]⁺ calcd for C₃₆H₄₁N₅O₇S, 688.27; found 688.3.-   (5-2)    N-{2-[4′-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)biphenyl-2-sulfonylamino]-2-oxoethyl}-N′-hydroxy-2-isobutylmalonamide.    MS m/z: [M+H]⁺ calcd for C₃₃H₄₃N₅O₇S, 654.29; found 654.5.-   (5-3)    4′-(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)biphenyl-2-sulfonic    acid ((S)-2-mercapto-4-methylpentanoyl)amide. MS m/z: [M+H]⁺ calcd    for C₃₀H₃₉N₃O₄S₂, 570.24; found 570.6.

Assay 1 AT₁ and AT₂ Radioligand Binding Assays

These in vitro assays were used to assess the ability of test compoundsto bind to the AT₁ and the AT₂ receptors.

Membrane Preparation from Cells Expressing Human AT₁ or AT₂ Receptors

Chinese hamster ovary (CHO-K1) derived cell lines stably expressing thecloned human AT₁ or AT₂ receptors, respectively, were grown in HAM's-F12medium supplemented with 10% fetal bovine serum, 10 μg/mlpenicillin/streptomycin, and 500 μg/ml geneticin in a 5% CO₂ humidifiedincubator at 37° C. AT₂ receptor expressing cells were grown in theadditional presence of 100 nM PD123,319 (AT₂ antagonist). When culturesreached 80-95% confluence, the cells were washed thoroughly in PBS andlifted with 5 mM EDTA. Cells were pelleted by centrifugation and snapfrozen in MeOH-dry ice and stored at −80° C. until further use.

For membrane preparation, cell pellets were resuspended in lysis buffer(25 mM Tris/HCl pH 7.5 at 4° C., 1 mM EDTA, and one tablet of CompleteProtease Inhibitor Cocktail Tablets with 2 mM EDTA per 50 mL buffer(Roche cat. #1697498, Roche Molecular Biochemicals, Indianapolis, Ind.))and homogenized using a tight-fitting Dounce glass homogenizer (10strokes) on ice. The homogenate was centrifuged at 1000×g, thesupernatant was collected and centrifuged at 20,000×g. The final pelletwas resuspended in membrane buffer (75 mM Tris/HCl pH 7.5, 12.5 mMMgCl₂, 0.3 mM EDTA, 1 mM EGTA, 250 mM sucrose at 4° C.) and homogenizedby extrusion through a 20 G gauge needle. Protein concentration of themembrane suspension was determined by the method described in Bradford(1976) Anal Biochem. 72:248-54. Membranes were snap frozen in MeOH-dryice and stored at −80° C. until further use.

Ligand Binding Assay to Determine Compound Affinities for the Human AT₁and AT₂ Angiotensin Receptors

Binding assays were performed in 96-well Acrowell filter plates (PallInc., cat. #5020) in a total assay volume of 100 μL with 0.2 μg membraneprotein for membranes containing the human AT₁ receptor, or 2 μgmembrane protein for membranes containing the human AT₂ receptor inassay buffer (50 mM Tris/HCl pH 7.5 at 20° C., 5 mM MgCl₂, 25 μM EDTA,0.025% BSA). Saturation binding studies for determination of K_(d)values of the ligand were done using N-terminally Europium-labeledangiotensin-II ([Eu]AngII,H-(Eu—N¹)-Ahx-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH; PerkinElmer, Boston,Mass.) at 8 different concentrations ranging from 0.1 nM to 30 nM.Displacement assays for determination of pK_(i) values of test compoundswere done with [Eu]AngII at 2 nM and 11 different concentrations of drugranging from 1 pM to 10 μM. Drugs were dissolved to a concentration of 1mM in DMSO and from there serially diluted into assay buffer.Non-specific binding was determined in the presence of 10 μM unlabeledangiotensin-II. Assays were incubated for 120 minutes in the dark, atroom temperature or 37° C., and binding reactions were terminated byrapid filtration through the Acrowell filter plates followed by threewashes with 200 μL ice cold wash buffer (50 mM Tris/HCl pH 7.5 at 4° C.,5 mM MgCl₂) using a Waters filtration manifold. Plates were tapped dryand incubated with 50 μl DELFIA Enhancement Solution (PerkinElmer cat.#4001-0010) at room temperature for 5 minutes on a shaker. Filter-bound[Eu]AngII was quantitated immediately on a Fusion plate reader(PerkinElmer) using Time Resolved Fluorescence (TRF). Binding data wereanalyzed by nonlinear regression analysis with the GraphPad PrismSoftware package (GraphPad Software, Inc., San Diego, Calif.) using the3-parameter model for one-site competition. The BOTTOM (curve minimum)was fixed to the value for nonspecific binding, as determined in thepresence of 10 μM angiotensin II. K_(i) values for drugs were calculatedfrom observed IC₅₀ values and the K_(d) value of [Eu]AngII according tothe Cheng-Prusoff equation described in Cheng et al. (1973) BiochemPharmacol. 22(23):3099-108. Selectivities of test compounds for the AT₁receptor over the AT₂ receptor were calculated as the ratio of AT₂K_(i)/AT₁K_(i). Binding affinities of test compounds were expressed asnegative decadic logarithms of the K_(i) values (pK_(i)).

In this assay, a higher pK_(i) value indicates that the test compoundhas a higher binding affinity for the receptor tested. Exemplarycompounds of the invention that were tested in this assay, typicallywere found to have a pK_(i) at the AT₁ receptor greater than or equal toabout 5.0. For example, the compound of Example 1 was found to have apK_(i) value greater than about 7.0.

Assay 2 In Vitro Assays for the Quantitation of Inhibitor Potencies(IC_(so)) at Human and Rat NEP, and Human ACE

The inhibitory activities of compounds at human and rat NEP and humanACE were determined using in vitro assays as described below.

Extraction of NEP Activity from Rat Kidneys

Rat NEP was prepared from the kidneys of adult Sprague Dawley rats.Whole kidneys were washed in cold PBS and brought up in ice-cold lysisbuffer (1% Triton X-114, 150 mM NaCl, 50 mM Tris pH 7.5; Bordier (1981)J. Biol. Chem. 256:1604-1607) in a ratio of 5 mL of buffer for everygram of kidney. Samples were homogenized using a polytron hand heldtissue grinder on ice. Homogenates were centrifuged at 1000×g in aswinging bucket rotor for 5 minutes at 3° C. The pellet was resuspendedin 20 mL of ice cold lysis buffer and incubated on ice for 30 minutes.Samples (15-20 mL) were then layered onto 25 mL of ice-cold cushionbuffer (6% w/v sucrose, 50 mM pH 7.5 Tris, 150 mM NaCl, 0.06%, TritonX-114), heated to 37° C. for 3-5 minutes and centrifuged at 1000×g in aswinging bucket rotor at room temperature for 3 minutes. The two upperlayers were aspirated off, leaving a viscous oily precipitate containingthe enriched membrane fraction. Glycerol was added to a concentration of50% and samples were stored at −20° C. Protein concentrations werequantitated using a BCA detection system with BSA as a standard.

Enzyme Inhibition Assays

Recombinant human NEP and recombinant human ACE were obtainedcommercially (R&D Systems, Minneapolis, Minn., catalog numbers 1182-ZNand 929-ZN, respectively). The fluorogenic peptide substrate Mca-BK2(Mca-Arg-Pro-Pro-Gly-Phe-Ser-Ala-Phe-Lys(Dnp)-OH; Johnson et al. (2000)Anal. Biochem. 286: 112-118) was used for the human NEP and ACE assays,and Mca-RRL (Mca-DArg-Arg-Leu-(Dnp)-OH; Medeiros et al. (1997) Braz. J.Med. Biol. Res. 30:1157-1162) was used for the rat NEP assay (both fromAnaspec, San Jose, Calif.).

The assays were performed in 384-well white opaque plates at roomtemperature using the respective fluorogenic peptides at a concentrationof 10 μM in Assay Buffer (50 mM Tris/HCl at 25° C., 100 mM NaCl, 0.01%Tween-20, 1 μM Zn, 0.025% BSA). Human NEP and human ACE were used atconcentrations that resulted in quantitative proteolysis of 5 μM ofMca-BK2 within 20 minutes at room temperature. The rat NEP enzymepreparation was used at a concentration that yielded quantitativeproteolysis of 3 μM of Mca-RRL within 20 minutes at room temperature.

Test compounds were diluted to 12 concentrations from 10 μM to 20 μM inAssay Buffer. Assays were started by adding 25 μL of enzyme to 12.5 μLof test compound at each of the 12 concentrations. Test compounds wereallowed to equilibrate with the enzyme for 10 minutes before 12.5 μL ofthe fluorogenic substrates were added to initiate the reaction.Reactions were terminated by the addition of 10 μL of 3.6% glacialacetic acid after 20 minutes of incubation.

For sulfhydryl-containing test compounds, the test compounds may bediluted in Assay Buffer containing a 400 μM concentration oftris(2-carboxyethyl)phosphine hydrochloride (Thermo Scientific,Rockford, Ill.) (TCEP). The test compounds are then allowed to reducefor 40 minutes at room temperature before adding the enzyme. Testcompounds are then allowed to equilibrate with the enzyme for 20 minutesbefore adding the fluorogenic substrates. Reactions are terminated asabove.

Plates were read on a fluorometer with excitation and emissionwavelengths set to 320 nm and 405 nm, respectively. Raw data (relativefluorescence units) were normalized to % activity from the average highreadings (no inhibition, 100% enzyme activity) and average low readings(full inhibition, highest inhibitor concentration, 0% enzyme activity)using three standard NEP and ACE inhibitors, respectively. Nonlinearregression of the normalized data was performed using a one sitecompetition model (GraphPad Software, Inc., San Diego, Calif.). Datawere reported as pIC₅₀ values.

Exemplary compounds of the invention that were tested in this assay,typically were found to have a pIC₅₀ for the NEP enzyme greater than orequal to about 5.0. For example, the compound of Example 1 has a pIC₅₀value greater than or equal to about 7.0.

Assay 3 Pharmacodynamic (PD) assay for ACE, AT₁, and NEP Activity inAnesthetized Rats

Male, Sprague Dawley, normotensive rats are anesthetized with 120 mg/kg(i.p.) of inactin. Once anesthetized, the jugular vein, carotid artery(PE 50 tubing) and bladder (URI-1 urinary silicone catheter) arecannulated and a tracheotomy is performed (Teflon Needle, size 14 gauge)to facilitate spontaneous respiration. The animals are then allowed a 60minute stabilization period and kept continuously infused with 5 mL/kg/hof saline (0.9%) throughout, to keep them hydrated and ensure urineproduction. Body temperature is maintained throughout the experiment byuse of a heating pad. At the end of the 60 minute stabilization period,the animals are dosed intravenously (i.v.) with two doses of angiotensin(AngI, 1.0 μg/kg, for ACE inhibitor activity; AngII, 0.1 μg/kg, for AT₁receptor antagonist activity) at 15 minutes apart. At 15 minutespost-second dose of angiotensin (AngI or AngII), the animals are treatedwith vehicle or test compound. Five minutes later, the animals areadditionally treated with a bolus i.v. injection of atrial natriureticpeptide (ANP; 30 μg/kg). Urine collection (into pre-weighted eppendorftubes) is started immediately after the ANP treatment and continued for60 minutes. At 30 and 60 minutes into urine collection, the animals arere-challenged with angiotensin (AngI or AngII). Blood pressuremeasurements are done using the Notocord system (Kalamazoo, Mich.).Urine samples are frozen at −20° C. until used for the cGMP assay. UrinecGMP concentrations are determined by Enzyme Immuno Assay using acommercial kit (Assay Designs, Ann Arbor, Mich., Cat. No. 901-013).Urine volume is determined gravimetrically. Urinary cGMP output iscalculated as the product of urine output and urine cGMP concentration.ACE inhibition or AT₁ antagonism is assessed by quantifying the %inhibition of pressor response to AngI or AngII, respectively. NEPinhibition is assessed by quantifying the potentiation of ANP-inducedelevation in urinary cGMP output.

Assay 4 In Vivo Evaluation of Antihypertensive Effects in the ConsciousSHR Model of Hypertension

Spontaneously hypertensive rats (SHR, 14-20 weeks of age) are allowed aminimum of 48 hours acclimation upon arrival at the testing site. Sevendays prior to testing, the animals are either placed on a restrictedlow-salt diet with food containing 0.1% of sodium for sodium depletedSHRs (SD-SHR) or are placed on a normal diet for sodium repleted SHRs(SR—SHR). Two days prior to testing, the animals are surgicallyimplemented with catheters into a carotid artery and the jugular vein(PESO polyethylene tubing) connected via a PE10 polyethylene tubing to aselected silicone tubing (size 0.020 ID×0.037 OD×0.008 wall) for bloodpressure measurement and test compound delivery, respectively. Theanimals are allowed to recover with appropriate post operative care.

On the day of the experiment, the animals are placed in their cages andthe catheters are connected via a swivel to a calibrated pressuretransducer. After 1 hour of acclimation, a baseline measurement is takenover a period of at least five minutes. The animals are then dosed i.v.with vehicle or test compound in ascending cumulative doses every 60minutes followed by a 0.3 mL saline to clear the catheter after eachdose. Data is recorded continuously for the duration of the study usingNotocord software (Kalamazoo, Mich.) and stored as electronic digitalsignals. In some studies, the effects of a single intravenous or oral(gavage) dose are monitored for at least 6 hours after dosing.Parameters measured are blood pressure (systolic, diastolic and meanarterial pressure) and heart rate.

Assay 5 In Vivo Evaluation of Antihypertensive Effects in the ConsciousDOCA-Salt Rat Model of Hypertension

CD rats (male, adult, 200-300 grams, Charles River Laboratory, USA) areallowed a minimum of 48 hours acclimation upon arrival at the testingsite before they are placed on a high salt diet.

One week after the start of the high salt diet, a DOCA-salt pellet (100mg, 21 days release time, Innovative Research of America, Sarasota,Fla.) is implanted subcutaneously and unilateral nephrectomy isperformed. On 16 or 17 days post DOCA-salt pellet implantation, animalsare implanted surgically with catheters into a carotid artery and thejugular vein with a PESO polyethylene tubing, which in turn wasconnected via a PE10 polyethylene tubing to a selected silicone tubing(size 0.020 ID×0.037 OD×0.008 wall) for blood pressure measurement andtest compound delivery, respectively. The animals are allowed to recoverwith appropriate post operative care.

On the day of the experiment, each animal is kept in its cage andconnected via a swivel to a calibrated pressure transducer. After 1 hourof acclimation, a baseline measurement is taken over a period of atleast five minutes. The animals are then dosed i.v. with a vehicle ortest compound in escalating cumulative doses every 60 minutes followedby 0.3 mL of saline to flush the catheter after each dose. In somestudies, the effects of a single intravenous or oral (gavage) dose istested and monitored for at least 6 hours after dosing. Data is recordedcontinuously for the duration of the study using Notocord software(Kalamazoo, Mich.) and stored as electronic digital signals. Parametersmeasured are blood pressure (systolic, diastolic and mean arterialpressure) and heart rate. For cumulative and single dosing, thepercentage change in mean arterial pressure (MAP, mmHg) or heart rate(HR, bpm) is determined as described for Assay 4.

While the present invention has been described with reference tospecific aspects or embodiments thereof, it will be understood by thoseof ordinary skilled in the art that various changes can be made orequivalents can be substituted without departing from the true spiritand scope of the invention. Additionally, to the extent permitted byapplicable patent statues and regulations, all publications, patents andpatent applications cited herein are hereby incorporated by reference intheir entirety to the same extent as if each document had beenindividually incorporated by reference herein.

1. A method for treating hypertension or heart failure, comprisingadministering to a patient a therapeutically effective amount of thecompound of formula Ia:

where: Y is:

Q is —C(R³)—, Z is a bond, and W is —N—; or Y is:

Q is —C(R³)—, Z is —C(O)—, and W is —N—; R¹ is selected from—C₁₋₆alkylene-OH, —COOR^(1a), —CHO, —C₁₋₃alkylene-NHCH(COOH)(C₁₋₆alkyl),—C(O)NHCH(COOH)(C₁₋₆alkyl), and —C(O)NHCH₂R^(1b); where R^(1a) is H or—C₁₋₆alkyl; and R^(1b) is —C₀₋₃alkylenearyl or —C₀₋₃alkyleneheteroaryl;R² is selected from H, —CH₂OH, halo, —NO₂, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₃₋₆cycloalkyl, —CN, —C(O)R^(2a), and —C₀₋₃alkylenearyl; where R^(2a)is H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —C₀₋₃alkylene-phenyl, —OR^(2b), or—NR^(2c)R^(2d); R^(2b) is H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, phenyl, orbenzyl; and R^(2c) and R^(2d) are independently H, —C₁₋₄-alkyl, or—C₀₋₁alkylene-phenyl; R³ is selected from —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₃₋₁₀alkynyl, —C₀₋₃alkylene-C₃₋₇cycloalkyl,—C₂₋₃alkenylene-C₃₋₇cycloalkyl, —C₂₋₃alkynylene-C₃₋₇cycloalkyl,—C₀₋₅alkylene-NR^(3a)—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-S—C₁₋₅alkylene-R^(3b), and —C₀₋₃alkylenearyl; R^(3a) is H,—C₁₋₆alkyl, —C₃₋₇cycloalkyl, or —C₀₋₃alkylenearyl; and R^(3b) is H,—C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, or aryl;Ar—X—CR⁵R⁶R⁷ is selected from:

X is selected from —SO₂NHC(O)—, —SO₂NHC(O)—C₁₋₁₂alkylene-NHC(O)—,—SO₂NHC(O)—C₁₋₁₂alkylene-C(O)NH—, —C(O)NH—SO₂—C₁₋₁₂alkylene-NHC(O)—,—C(O)NH—SO₂—C₁₋₁₂alkylene-C(O)NH—, —SO₂NHC(O)NH—C₂₋₁₂alkylene-NHC(O)—,—SO₂NHC(O)NH—C₁₋₁₂alkylene-C(O)NH—,—NH—SO₂—NHC(O)—C₁₋₁₂alkylene-NHC(O)—, and—NH—SO₂—NHC(O)—C₁₋₁₂alkylene-C(O)NH—; R⁵ is selected from—C₀₋₃alkylene-SR^(5a), —C₀₋₃alkylene-C(O)NR^(5b)R^(5c),—C₀₋₃alkylene-NR^(5b)—C(O)R^(5d), —NH—C₀₋₁alkylene-P(O)(OR^(5e))₂,—C₀₋₃alkylene-P(O)OR^(5e)R^(5f), —C₀₋₂alkylene-CHR^(5g)—-COON,—C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH, and —C₀₋₃alkylene-S—SR^(5j);R^(5a) is H or —C(O)R^(5aa); R^(5aa) is —C₁₋₆alkyl,—C₀₋₆alkylene-C₃₋₇cycloalkyl, —C₀₋₆alkylenearyl,—C₀₋₆alkyleneheteroaryl, —C₀₋₆alkylenemorpholine,—C₀₋₆alkylenepiperazine-CH₃, —CH[N(R^(5ab))₂]— aa where aa is an aminoacid side chain, -2-pyrrolidine, —C₀₋₆alkylene-OR^(5ab),—O—C₀₋₆alkylenearyl, —C₁₋₂alkylene-OC(O)—C₁₋₆alkyl,—C₁₋₂alkylene-OC(O)—C₀₋₆alkylenearyl, or—O—C₁₋₂alkylene-OC(O)O—C₁₋₆alkyl; R^(5ab) is H or —C₁₋₆alkyl; R^(5b) isH, —OH, —OC(O)R^(5ba), —CH₂COOH, —O-benzyl, -pyridyl, or—OC(S)NR^(5bb)R^(5bc); R^(5ba) is H, —C₁₋₆alkyl, aryl, —OCH₂-aryl,—CH₂O-aryl, or —NR^(5bb)R^(5bc); R^(5bb) and R^(5bc) are independently Hor —C₁₋₄alkyl; R^(5c) is H, —C₁₋₆alkyl, or —C(O)—R^(5ca); R^(5ca) is H,—C₁₋₆alkyl, —C₃₋₇cycloalkyl, aryl, or heteroaryl; R^(5d) is H,—C₁₋₄alkyl, —C₀₋₃alkylenearyl, —NR^(5da)R^(5db), —CH₂SH, or—O—C₁₋₆alkyl; R^(5da) and R^(5db) are independently H or —C₁₋₄-alkyl;R^(5e) is H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl,—C₃₋₇cycloalkyl, —CH(CH₃)—O—C(O)R^(ea),

R^(5ea) is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(5eb)R^(5ec), or—CH(NH₂)CH₂COOCH₃; R^(5eb) and R^(5ec) are independently H, —C₁₋₄-alkyl,or —C₁₋₃alkylenearyl, or are taken together as —(CH₂)₃₋₆—; R^(5f) is H,—C₁₋₄alkyl, —C₀₋₃alkylenearyl, —C₁₋₃alkylene-NR^(5fa)R^(5fb), or—C₁₋₃alkylene(aryl)-C₀₋₃alkylene-NR^(5fa)R^(5fb); R^(5fa) and R^(5fb)are independently H or —C₁₋₄alkyl; R^(5g) is H, —C₁₋₆alkyl,—C₁₋₃alkylenearyl, or —CH₂—O—(CH₂)₂—OCH₃; R^(5h) is H or —C₁₋₄alkyl;R^(5i) is H, —C₁₋₄-alkyl, or —C₀₋₃alkylenearyl; and R^(5j) is—C₁₋₆alkyl, aryl, or —CH₂CH(NH₂)COOH; R⁶ is selected from —C₁₋₆alkyl,—CH₂—O—(CH₂)₂—OCH₃, —C₁₋₆alkylene-O—C₁₋₆alkyl, —C₀₋₃alkylenearyl,—C₀₋₃alkyleneheteroaryl, and —C₀₋₃alkylene-C₃₋₇cycloalkyl; and R⁷ is Hor is taken together with R⁶ to form —C₃₋₈cycloalkyl; one —CH₂— in the—C₁₋₁₂alkylene- portion of X is optionally replaced with—C₄₋₈cycloalkylene- or phenylene; one or more —CH₂— moieties areoptionally replaced with a —NR⁴—C(O)— or —C(O)—NR⁴— moiety, where R⁴ isH, —OH, or —C₁₋₄alkyl; and one or more —CH₂-moieties are optionallysubstituted with —COOH or an amino acid side chain; each alkyl and eacharyl in R¹⁻⁶ is optionally substituted with 1 to 7 fluoro atoms; eachring in Ar—X—CR⁵R⁶R⁷ and each aryl and heteroaryl in R¹, R², R³, andR⁵⁻⁶ is optionally substituted with 1 to 3 substituents independentlyselected from —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo,—O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, phenyl,—NO₂, —NH₂—NH—C₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each alkyl, alkenyland alkenyl is optionally substituted with 1 to 5 fluoro atoms; or apharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein R¹ is —CH₂OH, —COOH, —CHO, —CH₂NHCH(COOH)(C₂₋₅alkyl),—C(O)NHCH(COOH)(C₂₋₅alkyl), or —C(O)NHCH₂R^(1b); where R^(1b) is—C₀₋₃alkylenephenyl or —C₀₋₁alkyleneheteroaryl.
 3. The method of claim1, wherein R² is H or halo.
 4. The method of claim 1, wherein R³ is—C₂₋₇alkyl.
 5. The method of claim 1, wherein one of the —CH₂— moietiesin X is replaced with a —NR⁴—C(O)— or —C(O)—NR⁴— group.
 6. The method ofclaim 1, wherein X is —SO₂NHC(O)— or —SO₂NHC(O)—C₁₋₉alkylene-NHC(O)—. 7.The method of claim 6, wherein X is selected from: —SO₂NHC(O)—;—SO₂NHC(O)CH[CH(CH₃)₂]—NHC(O)—; —SO₂NHC(O)CH₂—NHC(O)—;—SO₂NHC(O)-cyclohexylene-NHC(O)—; —SO₂NHC(O)(CH₂)₂—NHC(O)—;—SO₂NHC(O)CH₂—NHC(O)—CH₂—NHC(O)—; —SO₂NHC(O)(CH₂)₄—NHC(O)—;—SO₂NHC(O)(CH₂)₂—NHC(O)—CH₂—NHC(O)—;—SO₂—NHC(O)(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—;—SO₂NHC(O)(CH₂)₂—NHC(O)—CH₂—CH(COOH)—NHC(O)—; —SO₂—NHC(O)(CH₂)₆—NHC(O)—;—SO₂NHC(O)(CH₂)₂—NHC(O)—(CH₂)₂—CH(COOH)—NHC(O)—;—SO₂—NHC(O)(CH₂)₄—NHC(O)—CH₂—NHC(O)—; and—SO₂NHC(O)(CH₂)₆—NHC(O)—CH₂—NHC(O)—.
 8. The method of claim 1, whereinR⁵ is —C₀₋₃alkylene-SR^(5a), —C₀₋₃alkylene-C(O)NR^(5b)R^(5c),—C₀₋₃alkylene-NR^(5b)—C(O)R^(5d), —NH—C₀₋₁alkylene-P(O)(OR^(5e))₂,—C₀₋₃alkylene-P(O)OR^(5e)R^(5f), —C₀₋₂alkylene-CHR^(5g)—COOH, or—C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH; where R^(5a) is H, R^(5b) is—OH, R^(5c) is H, R^(5d) is H, and R^(5e) is H.
 9. The method of claim8, wherein R⁵ is —C₀₋₃alkylene-SH, —C₀₋₃alkylene-C(O)N(R^(5b))H,—NH—C₀₋₁alkylene-P(O)(OH)₂, or—C₀₋₂alkylene-CH[—CH₂—O—(CH₂)₂—OCH₃]—COOH.
 10. The method of claim 1,wherein R⁵ is —C₀₋₃alkylene-SR^(5a), —C₀₋₃alkylene-C(O)NR^(5b)R^(5c),—C₀₋₃alkylene-NR^(5b)—C(O)R^(5d), —NH—C₀₋₁alkylene-P(O)(OR^(5e))₂,—C₀₋₃alkylene-P(O)OR^(5e)R^(5f), or —C₀₋₃alkylene-S—SO; where R^(5a) is—C(O)_R^(5aa); R^(5b) is H, —OC(O)R^(5ba), —CH₂COOH, —O-benzyl,-pyridyl, or —OC(S)NR^(5bb)R^(5bc); and R^(5e) is —C₁₋₆alkyl,—C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl, —CH(CH₃)—OC(O)R^(5ea),


11. The method of claim 1, wherein R⁶ is —C₁₋₆alkyl.
 12. The method ofclaim 1, wherein R⁷ is H or is taken together with R⁶ to formcyclopentyl.
 13. The method of claim 1, having formula Ib:


14. The method of claim 13, wherein R¹ is —C₁₋₆alkylene-OH or —CHO; R²is H or halo; R³ is —C₁₋₁₀alkyl; X is —SO₂NHC(O)—C₁₋₉alkylene-NHC(O)—;R⁵ is —C₀₋₃alkylene-SH, —C₀₋₃alkylene-C(O)N(R^(5b))H,—NH—C₀₋₁alkylene-P(O)(OH)₂, or—C₀₋₂alkylene-CH[—CH₂—O—(CH₂)₂—OCH₃]-COOH, where R^(5b) is —OH or—OC(O)—C₁₋₆alkyl; R⁶ is —C₁₋₆alkyl or —C₀₋₃alkylenearyl; and R⁷ is H oris taken together with R⁶ to form —C₃₋₈cycloalkyl; where one —CH₂— inthe —C₁₋₉alkylene- portion of X is optionally replaced with—C₄₋₈cycloalkylene-; one —CH₂— moiety is optionally replaced with a—NHC(O)— moiety; one —CH₂— moiety is optionally substituted with —COOHor an amino acid side chain; and the aryl in R⁶ is optionallysubstituted with phenyl.
 15. The method of claim 1, having formula Ic:


16. The method of claim 15, wherein R¹ is —C₁₋₆alkylene-OH, —COOH, —CHO,—C₁₋₃alkylene-NHCH(COOH)(C₁₋₆alkyl), or —C(O)NHCH₂R^(1b), where R^(1b)is —C₀₋₃alkylenearyl or —C₀₋₃alkyleneheteroaryl; R² is halo; R³ is—C₁₋₁₀alkyl; X is —SO₂NHC(O)—C₁₋₉alkylene-NHC(O)—; R⁵ is—C₀₋₃alkylene-SH or —C₀₋₃alkylene-C(O)N(OH)H; R⁶ is —C₁₋₆alkyl or—C₀₋₃alkylenearyl; and R⁷ is H; where one —CH₂-moiety in the—C₁₋₉alkylene- portion of X is optionally replaced with a —NHC(O)—moiety.
 17. The method of claim 1, having formula Id:


18. The method of claim 17, wherein R³ is —C₁₋₁₀alkyl; X is —SO₂NHC(O)—or —SO₂NHC(O)—C₁₋₅alkylene-NHC(O)—; R⁵ is —C₀₋₃alkylene-SH or—C₀₋₃alkylene-C(O)N(OH)H; R⁶ is —C₁₋₆alkyl or —C₀₋₃alkylenearyl; and R⁷is H; where one —CH₂-moiety in the —C₁₋₅alkylene- portion of X isoptionally replaced with a —NHC(O)— moiety; and one —CH₂— moiety isoptionally substituted with an amino acid side chain.
 19. The method ofclaim 1, wherein R¹ is —C₁₋₆alkylene-OH, —COOH, —CHO,—C₁₋₃alkylene-NHCH(COOH)(C₁₋₆alkyl), or —C(O)NHCH₂R^(1b); where R^(1b)is —C₀₋₃alkylenearyl or —C₀₋₃alkyleneheteroaryl; R² is H or halo; R³ is—C₁₋₁₀alkyl; X is —SO₂NHC(O)— or —SO₂NHC(O)—C₁₋₉alkylene-NHC(O)—; R⁵ is—C₀₋₃alkylene-SH, —C₀₋₃alkylene-C(O)N(R^(5b))H,—NH—C₀₋₁alkylene-P(O)(OH)₂, or—C₀₋₂alkylene-CH[—CH₂—O—(CH₂)₂—OCH₃]-COOH; where R^(5b) is —OH or—OC(O)—C₁₋₆alkyl; R⁶ is —C₁₋₆alkyl or —C₀₋₃alkylenearyl; and R⁷ is H oris taken together with R⁶ to form —C₃₋₈cycloalkyl; where one —CH₂— inthe —C₁₋₉alkylene- portion of X is optionally replaced with—C₄₋₈cycloalkylene-; one —CH₂— moiety is optionally replaced with a—NHC(O)— moiety; one —CH₂— moiety is optionally substituted with —COOH;and the aryl in R⁶ is optionally substituted with phenyl.
 20. The methodof claim 19, wherein R¹ is —CH₂OH, —COOH, —CHO,—CH₂NHCH(COOH)[CH₂CH(CH₃)₂], —C(O)NHCH₂-phenyl, —C(O)NH(CH₂)₂-phenyl,—C(O)NH(CH₂)₃-phenyl, —C(O)NH(CH₂)₄-phenyl, —C(O)NHCH₂-2-thienyl, or—C(O)NH(CH₂)₂₋₂-thienyl; R² is H or chloro; R³ is —(CH₂)₃CH₃; X isselected from: —SO₂NHC(O)—; —SO₂NHC(O)CH[CH(CH₃)₂]—NHC(O)—;—SO₂NHC(O)CH₂—NHC(O)—; —SO₂NHC(O)-cyclopentylene-NHC(O)—;—SO₂NHC(O)-cyclohexylene-NHC(O)—; —SO₂NHC(O)(CH₂)₂—NHC(O)—;—SO₂NHC(O)CH₂—NHC(O)—CH₂—NHC(O)—; —SO₂NHC(O)(CH₂)₄—NHC(O)—;—SO₂NHC(O)(CH₂)₂—NHC(O)—CH₂—NHC(O)—;—SO₂—NHC(O)(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—;—SO₂NHC(O)(CH₂)₂—NHC(O)—CH₂—CH(COOH)—NHC(O)—; —SO₂—NHC(O)(CH₂)₆—NHC(O)—;—SO₂NHC(O)(CH₂)₂—NHC(O)—(CH₂)₂—CH(COOH)—NHC(O)—;—SO₂—NHC(O)(CH₂)₄—NHC(O)—CH₂—NHC(O)—; and—SO₂NHC(O)(CH₂)₆—NHC(O)—CH₂—NHC(O)—; R⁵ is —SH, —CH₂—SH, —C(O)NH(OH),—C(O)NH[OC(O)CH₃], —C(O)NH[OC(O)C(CH₃)₃], —NH—CH₂—P(O)(OH)₂, or—CH₂—CH[CH₂—O—(CH₂)₂—OCH₃]-COOH; R⁶ is —CH₃, —CH(CH₃)₂, —CH(CH₃)CH₂CH₃,—CH₂CH(CH₃)₂, —CH₂-phenyl, or —CH₂-biphenyl; and R⁷ is H or is takentogether with R⁶ to form cyclopentyl.